Synthesis and SAR studies of trisubstituted purinones as potent and selective adenosine A2A receptor antagonists

History and Perspectives of A2AAdenosine Receptor Antagonists as Potential Therapeutic Agents

“…The second-generation lead gave evidence for a promising safety and pharmacokinetic profile in healthy volunteers during a Phase I trial (see Section 6). 101 Some C 2 -, N 7 -, and N 9 -trisubstituted-purin-8-ones (i.e., 54 K i hA 2A AR = 9 nM, K i hA 1 AR = 1967, IC 50 rA 2A AR = 18 nM), 175 2-alkynyl-N 9 -propargyl adenine derivatives (i.e., 55 K i hA 2A AR = 0.56 nM, K i hA 2B /K i hA 2A ARs = 1.300, K i hA 1 /K i hA 2A ARs = 10), 176,177 and 7-amino-2-arylpyrazolo[4,3-d]pyrimidine derivatives (i.e., 56, K i hA 2A AR = 55 nM, K i hA 1 AR = 5.3 nM) 178 have been reported as examples of purine-related A 2A antagonists or A 1 /A 2A dual antagonists.…”

Regioselective Control of the SNAr Amination of 5-Substituted-2,4-Dichloropyrimidines Using Tertiary Amine Nucleophiles

“…2,4-Dichloropyrimidines that are further substituted at C-5 with an electron-withdrawing substituent (notably cyano, nitro, or trifluoromethyl) are particularly useful starting materials, yielding (upon further synthetic transformation) pyrimidine-containing structures with biological activity. The breadth of biologically active pyrimidine, and pyrimidine-derived, structures is expansive. , The synthetic objectives of several examples are cited herein: adenosine A 2A receptor antagonist; HIV non-nucleoside reverse transcriptase inhibitor; VLA-4 integrin antagonist; inhibitor of falcipain protease; inhibitor of stearoyl-CoA desaturase; and inhibitors of human kinases. − The S N Ar reactions of these pyrimidines (whether with carbon, nitrogen, or oxygen nucleophiles) invariably occur rapidly (often in minutes) at low temperatures (ambient and below), with excellent yields and outstanding regioselectivity for nucleophilic displacement of the C-4 halogen . Indeed, with many amine nucleophiles, this regioselectivity is so good that the accompanying experimentals often fail to acknowledge the possible presence of a minor product from competing substitution at C-2.…”

“…Indeed, with many amine nucleophiles, this regioselectivity is so good that the accompanying experimentals often fail to acknowledge the possible presence of a minor product from competing substitution at C-2. Where the ratio for C-4 compared to C-2 substitution of 2,4-dichloro-5-nitropyrimidine 1 has been measured with sterically unencumbered amines, ratios between 9:1 to 19:1 are observed. ,− As the initial reaction of longer synthetic sequences, this reaction dictates the overall synthetic strategy. As the C-4 regioselectivity is not always desirable, effort has been given to the use of a Lewis acid (such as ZnCl 2 ) to direct amine nucleophiles toward preferential substitution at C-2 of the pyrimidine. , Here, we report a simple alternative toward this same objective: the use of a tertiary amine as the S N Ar nucleophile.…”

“…The breadth of biologically active pyrimidine, and pyrimidine-derived, structures is expansive. 1,2 The synthetic objectives of several examples are cited herein: adenosine A 2A receptor antagonist; 3 HIV non-nucleoside reverse transcriptase inhibitor; 4 VLA-4 integrin antagonist; 5 inhibitor of falcipain protease; 6 inhibitor of stearoyl-CoA desaturase; 7 and inhibitors of human kinases. 8−21 The S N Ar reactions of these pyrimidines (whether with carbon, nitrogen, or oxygen nucleophiles) invariably occur rapidly (often in minutes) at low temperatures (ambient and below), with excellent yields and outstanding regioselectivity for nucleophilic displacement of the C-4 halogen.…”

Regioselective and Facile Synthesis of 7,9-Dialkyl-8-oxopurines from 7,9-Dialkyl-7,8-dihydropurines: Total Synthesis of Heteromines I and J

“…For instance, antitumor 6 and antiviral 7 activities have been recently reported. 8-Oxopurines have also been used as antagonists of corticotropin-releasing hormone receptor, 8 corticotropin-releasing factor 1 receptor, 9 adenosine A 2A receptor, 10 and an agonist of toll-like receptor 7. 11 8-Oxopurines labeled with the 11 C isotope have been used for positron emission tomography imaging.…”