Quinoxalin-2-carboxamides: synthesis and pharmacological evaluation as serotonin type-3 (5-HT₃) receptor antagonists

Figures & data

Figure 1.  Pharmacophore of 5-HT₃ receptor antagonists.

Figure 2.  Ondansetron.

Table 1.  Physical constants and pharmacological data of quinoxalin-2-carboxamides.

Compound	R	%Yield	mp In °C	Antagonism to 2-Me-5-HT (pA2)^a	Log P^b
4a	C6H5-	70	128–130	7.3	2.84
4b	o-MeO-C6H4-	63	148–150	4.5	2.71
4c	p-MeO-C6H4-	52	94–96	5.0	2.71
4d	p-Cl-C6H4-	71	124–126	5.0	3.39
4e	m-Cl-C6H4-	81	63–65	4.8	3.39
4f	m-CF3-C6H4-	65	150–152	4.5	3.76
4g	C6H5-CH2-	74	216–220^c	7.8	2.49
4h	CH3-	64	Semisolid	6.3	0.79
4i	CH3-CH2-	66	240–242^c	5.9	1.10
4j	CH2=CH-CH2-	68	Semisolid	4.5	1.45
5a	(CH3)2N-CH2-CH2-	54	44–46	5.9	0.77
5b	2-(Indol-3-yl)ethyl-	79	146–150	7.3	2.32
5c	p-N(C2H5)2–C6H4-	78	240–242^c	7.0	3.39
5d	3-Pridyl-	49	186–188	6.7	1.10
Ondansetron	—	—	—	6.9	—

^apA₂ values are the means of two separate experiments. SE was less than 10% of the mean.

^bLog P values were calculated by using ChemBioDraw Ultra 11 (Cambridge Software).

^cMelting points are taken as hydrochloride salts.

SE, standard error of mean.

Scheme 1.  Reagents and conditions: (A) D-fructose, 10% aq. AcOH, 80°C, 18 h; (B) NaOH, 30% H₂O₂, 60°C, 3 h then 90°C, 2 h, (C) Conc. HCl; (D) EDC HCl, HOBt, THF, N₂, 0°C–RT, 1 h; (E) piperazine, RT, 5 h; (F) R-NH₂, RT, 5 h. THS, tetrahydrofuran