Chapter I. Synthesis, modification and bioactivity of bicyclic thieno[3,2-D]pyrimidines

1.1.19.1.1 The C-2 alkyl derivatives 20 and 21
The C-2 alkyl derivatives 20 and 21, were prepared in a related manner, though the precursor 2-alkyl-4-chlorothienopyrimidines required bespoke synthesis from aminothiophene 31, as detailed in Scheme 3. N-Acylation of 31 with the appropriate alkyl anhydride introduced the desired aliphatic moiety and the resultant bis-amide was cyclised under basic conditions then converted to the corresponding 4-chlorothienopyrimidine with phosphorous oxychloride. The thiophene ketone moiety was then introduced via the aforementioned N,N-dimethylimidazolium iodide-mediated coupling[66, 67].

Reagents and conditions: (a) (RCO)2O, PhCH3, NEt3, reflux, 1.5 h, 80–82%; (b) NaOH, reflux, 4 h, 100%; (c) POCl3, reflux, 4 h, 72–92%; (d) thiophene-2-carboxaldehyde, N,N-dimethylimidazolium iodide, NaH, THF, reflux, 15 min, 54–66%.
In summary, we report herein the discovery of a novel class of adenosine A2A antagonists. Through iterative medicinal chemistry, we have demonstrated that 4-ketoarylthieno[3,2-d]pyrimidine derivatives show strong antagonism of the human adenosine A2A receptor and selectivity against the A1 receptor. Furthermore, some of these compounds have demonstrated activity in a commonly used in vivo model predictive of potential utility for the treatment of Parkinson’s disease[68].
The compounds employed in these studies were prepared as described below. 7 Compound 3 was prepared as described in Scheme. Cyclisation of 3-aminothiophene-2-carboxylate methyl ester 43 with urea gave diol 44, the chlorination of which yielded 2,4-dichlorothieno[3,2-d]pyrimidine 45. The treatment of 45 with thiophene-2- boronic acid under standard Suzuki coupling conditions then gave regioselective access to the desired C-4 substituted regioisomer. The compounds employed in these studies were prepared as described below. 7 Compound 3 was prepared as described in Scheme. Cyclisation of 3-aminothiophene-2-carboxylate methyl ester 43 withurea gave diol 44, the chlorination of which yielded 2,4-dichlorothieno[3,2-d]pyrimidine 45. The treatment of 45 with thiophene-2-boronic acid under standard Suzuki coupling conditions then gave regioselective access to the desired C-4 substituted regioisomer. Similarly, the cyclisation of 3-aminothiophene-2-carboxamide 46 with propionic anhydride, followed by chlorination with phosphorous oxychloride yielded 4-chloro-2-ethylthieno[3,2-d]pyrimidine 47. Suzuki coupling with thiophene-2-boronic acid gave. The methoxy derivative 5 and the amino derivatives 6–8 were prepared via the 2-chloro precursor3, by heating rothieno[3,2-d]pyrimidine 45. Coupling with the desired heterocycle under Suzuki, Stille or Negishi conditions was followed by the displacement of the 2-Cl with the relevant amine, in the manner illustrated in scheme. Compounds 36–42 were all prepared via methodology similar to the preparation of 11, 24 and 25.The further evolution of this series is reported in the following communication[69].
Reagents and conditions: (a) urea, 200 C, 4 h, 83%; (b) PhPOCl2, 170 C, 2 h, 66%; (c) Pd(OAc)2, PPh3, THF, rt, 5 min then thiophene-2-boronic acid, satdaq NaHCO3, reflux, 4 h, 94%.

Reagents and conditions: (a) sodium methoxide, reflux, 18 h, 95%; (b) NHR1 R2 , NMP, 90 C, 16 h, 42–77%

Reagents and conditions: (a) (compound 9) PdCl2(PPh3)2, DMF, Ar–SnBu3, rt, 16 h, 56%; (b) (compound 10) Pd(OAc)2, PPh3, THF, rt, 5 min then aryl boronic acid, satdaq NaHCO3, reflux, 4 h, 36–52%; (c) (compounds 11–16); (i) heterocycle, THF, n-BuLi, 78 C, 15 min then ZnCl2, Et2O, 78 C to rt; (ii) 47, Pd(PPh3)4, reflux, 17 h, 37–65%.

Reagents and conditions: (a) (compounds 17–22, 32 and 33) PdCl2(PPh3)2, DMF, Ar–SnBu3, rt, 16 h, 31–67%; (b) (compound 23) Pd(OAc)2, PPh3, THF, rt, 5 min then aryl boronic acid, satdaq NaHCO3, reflux, 4 h, 33%; (c) (compounds 24–31 and 34); (i) heterocycle, THF, n-BuLi, 78 C, 15 min then ZnCl2, Et2O, 78 C to rt; (ii) 45, Pd(PPh3)4, reflux, 17 h, 22–87%; (d) NHR1 R2 , NMP, 90 C, 16 h, 13–100%.
In summary, 4-arylthieno[3,2-d]pyrimidines, serendipitously discovered as byproducts in the preparation of a related compound series, have been shown to display strong functional antagonism of the human A2A receptor. Optimisation of this series has led to A2A antagonists with low nM affinity and a high degree of selectivity over other adenosine receptor sub-types. Moreover, a number of these compounds show promising activity in vivo suggesting that they may have potential for the treatment of Parkinson’s disease. The further evolution of this series is reported in the following communication.