SOLID-STATE STRUCTURES AND CONFORMATIONAL STUDIES OF 4 1,2,3,4-TETRAHYDROACRIDINE ALZHEIMERS-DISEASE THERAPEUTICS

The solid-state structures of four 1,2,3,4-tetrahydroacridines [tacrin e hydrochloride monohydrate (1), 7-methoxytacrine hydrochloride monohy drate (2), velnacrine hydrogenmaleate (3) and suronacrine hydrogenmale ate (4)] were determined from single-crystal X-ray diffraction analysi s. (1): monoclinic, P2(1)/n, a = 8.778(1), b = 8.521(1), c = 17.603(2) angstrom, beta = 101.34(1)-degrees. (2): monoclinic, C2/c, a = 12.326 (7), b = 18.050(9), c = 13.822(8) angstrom, beta = 113.70(4)-degrees. (3): triclinic, P1BAR, a = 7.349(2), b = 9.417(3), c = 12.557(4) angst rom, alpha = 109.62(2), beta = 98.12(2), gamma = 101.18(2)-degrees. (4 ): monoclinic, P2(1)/n, a = 8.513(6), b = 18.74(1), c = 13.401(6) angs trom, beta = 91.21(5)-degrees. Final R factors for compounds (1)-(4) a re 0.047, 0.057, 0.057, 0.11, respectively. The overall arrangement of the common aminotetrahydroacridine skeleton looks similar in all deri vatives. However, whereas enantiomerization of the unsubstituted cyclo hexenyl rings occurs in (1) and (2), only quasi-axially hydroxyl subst ituted diastereomers are found for (3) and (4). This is presumably due to the different propensities for hydrogen bonding of axially vs. equ atorially disposed hydroxyl groups with the hydrogenmaleate anions. Em pirical and semiempirical calculations were performed to examine the c onformational behavior of the four compounds, both in vacuo and in sol ution.