Synthesis of N-Substituted Imidoethyl-3-aminomethyl-2,3-dihydro-1,4-dioxino[2,3-b]pyridines

A Series of N4-Imidoethyl Derivatives of 1-(2,3-Dihydro-1,4-benzodioxin-5-yl)piperazine as 5-HT1A Receptor Ligands: Synthesis and Structure-Affinity Relationships

“…The results of the in vitro binding studies in rat frontal cortex homogenates of the target compounds [7][8][9][10][11][12][13][14][15][16][17][18] are summarized in Table 2. Succinimidyl compound 7 has only a moderate affinity for the 5-HTia receptor (pX¡ = 6.96).…”

“…Introduction of a double bond located at positions 5-6 slightly decreases the affinity (compound 10, pX¡ = 8.00). The unsaturated maleic analog (11) of the saturated parent compound 7 shows a 9-fold decrease in affinity (pX; = 6.01 vs 6.96). Methylation of the maleic ring results in a considerable enhancement of the affinity (12, pX = 7.20).…”

“…NMR (DMSO-CDClg, 4:1) ó 2.21 (m, 2 H), 2.44 (m, 2 ), 3.12-3.43 (cluster, ethyl]-lFf-pyrrole-2,5-dione (11). Compound 11 was prepared from the piperazineethanamine 20 and maleic anhydride: yield 80%; mp 127-9 °C; NMR (CDClg) ó 2.61 (t, 2 H, NC772CH2, =7 = 7), 2.68 (m, 4 H, CH2 pip), 3.02 (br, 4 H, CH2 pip), 3.69 (t, 2 H, CH2C772N(C=0)2, =7 = 7), 4.23 (m, •2 H, Bzd H-2,3), 4.32 (m, 2 H, Bzd H-2,3), 6.52 (dd, 1 H, Bzd H-6, =7=8, 1), 6.58 (dd, 1 H, Bzd H-8, =7 = 8, 1), 6.70 ethyl]-3-methyl-lff-pyrrole-2,5-dione, Dihydrochloride (12).…”

“…Compound 13 was prepared using 3,4,5,6-tetrahydrophthalic anhydride and the piperazineethanamine 20. The free base was converted to its dihydrochloride salt: yield 67%; mp 245-7 °C; NMR (DMSO-CDClg, 4:1) <5 1.72 (m, 4 H, imid H-5,6), 2.27 (m, 4 H, imid H-4,7), 3.13 (m, 2 , Hax CH2 pip), 3.24 (m, 2 H, Hax CH2 pip), 3.36 (br, 2 H, +NHCH2CH2), 3.51 (m, 2 H, Heq CH2 pip), 3.65 (m, 2 H, He" CH2 pip), 3.66 (t, 2 H, CH2CH2N(C=0)2, =7 = 6), 4.24 (m, 4 H, Bzd H-2,3), 6.51 (dd, 1 H, Bzd H-6, =7=8, 1), 6.56 (dd, 1 H, Bzd H-8, =7 = 8, 1), 6.74 (t, 1 H, Bzd H-7, =7 = 8), 11.0 (br, 1 H, +NH). Anal.…”

“…[3][4][5][6] The discovery of other heteroarylpiperazines as potent 5-HTia ligands such as N4substituted derivatives of eltoprazine (3) and 4, e.g., the phenylbutyl derivative 5, and flesinoxan (6) has resulted in the pharmacological evaluation of these drugs as potential central nervous system (CNS) drugs. [7][8][9][10] In this paper the synthesis of a new series of N4imidoethyl derivatives (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) of eltoprazine (3) and their affinity for the 5-HTia receptor are described. The correlation of the inhibition constant pif, or the local inhibition constant pKi+ with the pKa and clogP was investigated.…”