2,6,8-Trisubstituted 1-deazapurines as adenosine receptor antagonists

Article abstract of DOI:10.1021/jm0607956

In this study we developed a refined pharmacophore model for antagonists of the human adenosine A₁ receptor, based on features of known pyrimidine and purine derivatives. The adoption of these updated criteria assisted us in synthesizing a series of 1-deazapurines with consistently high affinity as inverse agonists for the adenosine A₁ receptor. These 1-deazapurines (otherwise known as 3H-imidazo[4,5-b]pyridines) were substituted at their 2- and 6-positions, yielding a series with five of the derivatives displaying K_i values in the subnanomolar range. The most potent of these, compound 10 (LUF 5978), displayed an affinity of 0.55 nM at the human adenosine A₁ receptor with > 300-fold and 45-fold selectivity toward A_2A and A₃ receptors, respectively. Compound 14 (LUF 5981, K_i = 0.90 nM) appeared to have the best overall selectivity with respect to adenosine A_2A (> 200-fold) and A ₃ (700-fold) receptors.

Full text of DOI:10.1021/jm0607956

Supplementary material
2,6,8-Trisubstituted-1-Deazapurines as Adenosine Receptor Antagonists.
Lisa C. W. Chang, Jacobien Frijtag Drabbe Künzel*, Thea Mulder-Krieger, Joost Westerhout,
Thomas Spangenberg, Johannes Brussee, Adriaan P. IJzerman
Contents:
• experimental and spectroscopic data of compounds 6-12, 14
• elemental analyses of compounds 1-14
S1

Experimental and spectroscopic data of compounds 6-12, 14
2,6-Diphenyl-8-methyl-1-deazapurine (6)
Yield 87 %. mp 188-192 ºC; 1H NMR (CDCl3): 8.16-8.03 (m, 4H, Ph), 7.77 (s, 1H C1-H), 7.59-
13
7.47 (m, 6H, Ph), 2.01 (s, 3H, CH3). C-NMR (CDCl3): 153.9, 151.8, 150.5, 140.3, 139.6, 136.3,
133.1, 129.0, 128.8, 128.6, 127.7, 114.6, 14.9. MS (ES+): 286.0 Da.
2,6-Diphenyl-8-ethyl-1-deazapurine (7)
Yield 36 %. mp 188-192 ºC; 1H NMR (CDCl3 + MeOD): 7.93-7.87 (m, 4H, Ph), 7.62 (s, 1H C1-
H), 7.42-7.36 (m, 6H, Ph), 2.72 (q, 2H, J = 7.3 Hz, CH2), 1.22 (t, 3H, J = 7.3 Hz, CH3). 13C-NMR
(CDCl3 + MeOD): 159.1, 152.1, 139.8, 136.0, 130.8, 128.7, 128.6, 128.5, 128.3, 127.1, 114.7, 22.5,
12.0. MS (ES+): 300.0 Da.
2,6-Diphenyl-8-propyl-1-deazapurine (8)
1
Yield 29 %. mp 156-158 ºC; H NMR (MeOD): 8.05-8.04 (m, 2H, Ph), 8.00-7.89 (m, 2H, Ph),
7.70 (s, 1H C1-H), 7.54-7.35 (m, 6H, Ph), 2.88 (t, 2H, J = 7.3 Hz, CH2), 1.88 (m, 2H, CH2), 1.01 (t,
13
3H, J = 7.3 Hz, CH3). C-NMR (CDCl3): 153.4, 151.6, 150.0, 141.3, 137.4, 129.7, 129.4, 128.0,
115.3, 31.8, 22.6, 13.8. MS (ES+): 314.0 Da.
2,6-Diphenyl-8-isopropyl-1-deazapurine (9)
1
Yield 71 %. mp 232-234 ºC; H NMR (MeOD + CDCl3): 8.01-7.99 (m, 2H, Ph), 7.97-7.87 (m,
2H, Ph), 7.66 (s, 1H C1-H), 7.49-7.37 (m, 6H, Ph), 3.29-3.22 (m, 1H, CH), 1.43 (d, 6H, J = 7.3 Hz, 2
13
× CH3). C-NMR (DMSO): 162.1, 150.4, 150.2, 139.6, 137.1, 136.1, 131.6, 129.1, 128.7, 128.5,
128.3, 126.7, 112.2, 29.0, 21.1. MS (ES+): 314.0 Da.
2,6-Diphenyl-8-isobutyl-1-deazapurine (10)
1
Yield 65 %. mp 179-181 ºC; H NMR (CDCl3): 8.22-8.19 (m, 2H, Ph), 8.10-8.06 (m, 2H, Ph),
7.80 (s, 1H C1-H), 7.55-7.44 (m, 6H, Ph), 2.24 (d, 2H, J = 7.3 Hz, CH2), 1.86-1.80 (m, 1H, CH),
13
0.64 (d, 6H, J = 5.8 Hz, 2 × CH3). C-NMR (CDCl3): 157.2, 151.7, 150.4, 140.4, 139.5, 136.3,
133.1, 129.2, 128.7, 17.7, 114.6, 38.1, 22.1. MS (ES+): 328.0 Da.
S2

2,6-Diphenyl-8-(1-ethylpropyl)-1-deazapurine (11)
1
Yield 39 %. mp 196-197 ºC; H NMR (CDCl3): 8.27-8.24 (m, 2H, Ph), 8.11-8.07 (m, 2H, Ph),
7.82 (s, 1H C1-H), 7.57-7.43 (m, 6H, Ph), 2.37-2.30 (m, 1H, CH), 1.53-1.43 (m, 4H, 2 × CH2), 0.70-
0.63 (m, 6H, 2 × CH3). 13C-NMR (CDCl3): 160.3, 151.8, 150.0, 140.4, 139.2, 136.4, 132.7, 129.3,
128.9, 128.8, 128.5, 127.5, 114.3, 43.5, 26.6, 11.7. MS (ES+): 342.0 Da.
2,6-Diphenyl-8-tButyl-1-deazapurine (12)
1
Yield 76 %. mp 233-234 ºC; H NMR (CDCl3): 8.33-8.29 (m, 2H, Ph), 8.01-7.98 (m, 2H, Ph),
7.82 (s, 1H C1-H), 7.55-7.41 (m, 6H, Ph), 1.44 (s, 9H, 3 × CH3). 13C-NMR (CDCl3): 163.8, 152.1,
150.1, 140.2, 139.0, 138.2, 136.2, 132.3, 129.3, 128.9, 128.8, 128.7, 128.4, 128.3, 127.4, 114.1, 33.6,
28.9. MS (ES+): 328.0 Da.
Cyclohexane carboxylic anhydride12
Cyclohexane carboxylic acid (1.24 mL, 10 mmol) was ground together with K2CO3 (6 g) for
approx. 5 min. Tosyl chloride (0.95 g, 5 mmol, 0.5 eq.) was then added portionwise with a few drops
of EtOAc. Grinding was continued for approx. 40 min. The solids were then washed with CH2Cl2 (3
1
× 20 mL), filtered and the filtrate concentrated. Yield 26 %. H NMR (CDCl3): 2.46-2.33 (m, 2H,
CH), 1.99-1.23 (m, 20H, cHex).
2,6-Diphenyl-8-cyclohexyl-1-deazapurine (14)
1
Yield 49 %. mp 210-213 ºC; H NMR (CDCl3): 8.32-8.22 (m, 2H, Ph), 8.11-8.08 (m, 2H, Ph),
13
7.83 (s, 1H C1-H), 7.55-7.45 (m, 6H, Ph), 2.51-2.44 (m, 1H, CH), 1.10-1.06 (m, 10 H, cHex). C-
NMR (CDCl3): 161.4, 151.8, 150.2, 140.2, 139.4, 136.4, 129.3, 129.0, 128.8, 128.6, 127.5, 114.3,
38.6, 31.3, 25.7. MS (ES+): 354.0 Da.
S3