Optimisation of novel 4, 8-disubstituted dihydropyrimido[5,4-b][1,4]oxazine derivatives as potent GPR 119 agonists

Figures & data

Figure 1. The design of target compounds.

Scheme 1. Synthesis of compounds 10–13. Reagents and conditions: (a) 4-amino-3-fluorobenzonitrile, K₂CO₃, DMF, 65 °C, overnight. (b) 1 M BBr₃ in DCM, anhydrous DCM, r. t. – reflux, 2 h. (c) 1-bromo-2-chloroethane, K₂CO₃, DMF, 40 °C, overnight. (d) amines 3–6, Pd₂(dba)₃, X-Phos, Cs₂CO₃, 1,4-Dioxane, reflux, under N₂ overnight.

Scheme 2. Synthesis of compounds 15–20. Reagents and conditions: (a) 3 M HCl in EtOH, r. t., overnight. (b) chloro-fragments, Et₃N, DCM, r. t., overnight or Cs₂CO₃, DMF, r. t., overnight.

Scheme 3. Synthesis of compounds 22–25. Reagents and conditions: (a) 3 M HCl in EtOH, r. t., overnight. (b) chloro-fragments, Et₃N, DCM, r. t., overnight or Cs₂CO₃, DMF, r. t., overnight.

Table 1. GPR119 agonistic activities of compounds 10–13.

Compound	Structure	GPR119 activation		ClogP^b
		EC50 (nM)	%max^a
10		13	83.9	4.0
11		1800	45.9	4.6
12		200	63.5	3.5
13		>10000	22.7	4.5
GSK-1292263		6.6	100

^a %max: cAMP stimulation % compared to maximal effect of GSK1292263.

^b ClogP was calculated using ACD software from Discovery Studio 4.5.

Table 2. GPR119 agonistic activities of compounds 15–20 and 22–25.

Compound	Structure	GPR119 activation		ClogP^b
		EC50 (nM)	%max^a
15		12	146.3	3.8
16		130	60.5	4.6
17		250	71.2	4.3
18		110	100	3.0
19		68	75.6	3.7
20		82	79.6	3.3
22		120	66.1	3.3
23		44	70.7	4.0
24		40	62.7	3.8
25		90	100	2.7
GSK-1292263		6.6	100

^a %max: cAMP stimulation % compared to maximal effect of GSK1292263.

^b ClogP was calculated using ACD software from Discovery Studio 4.5.

Figure 2. Single dose of compounds 10 and 15 on oGTT in C57BL/6N mice. The results are presented as the mean ± SE. *p < 0.05 compared to vehicle group (n = 8).