Structure-Activity Relationships of Inotropk Bipyridines: CrystalSographic Analysis of Four Milrimone Analogues

摘要

l,6-Dihydro-2'-methyl-6-oxo-[3,4'-bipyridine]-5-carbo-nitrile (I), Ci_2H_9N_3O, Mr = 211.23, monoclinic, C2/c, a = 13.152(2), b = 8.987(2), c = 16.538 (3) A, B = 95.60(1)°, V= 1945.4(5) A3,Z = 8,Dx = 1.442Mgnr3, {MoKa} = 0.71073 A, f2, = 0.090 mm~(-1), F(000) = 880, T = 90 K, R = 0.066 for 1997 observed reflections. l,6-Dihydro-2,2'-dimethyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile (II), C13H11N3O, Mr = 225.25, triclinic, PI, a = 6.704(1), b = 6.846(1), c = 13.273 (3) A, a = 81.31 (2), 3 = 85.28 (2), 7 = 66.02 (2)°, V = 550.0 (2) A3, Z = 2, Dx = 1.360MgnT3, I(MoKa) = 0.71073A, p, = 0.084 mm~(-1), F(000) = 236, T = 90 K, R = 0.056 for 2301 observed reflections. 5-Amino-2-methyl-[3,4'-bipyridin]-6(l/f)-one (III), CnHnN_3O.HC_(l.2)H_2O, Mr = 273.72, triclinic, PI, a = 7.200(2), b = 10.695(2), c = 17.556 (4) A, a = 77.20(2), /3 = 87.94(2), 7 = 83.58 (2)°, 7=1310.0(7) A3, Z = 4, E* = 1-388 MgnT_3, A(Mo Ka) = 0.71073 A, JJ, = 0.293 mm~(-1), F(000) = 576, T = 291 K, R = 0.067 for 4921 reflections. 5-Amino-2'-methyl-[3,4/-bipyridin]-6(lH)-one (IV), CnHuN3O, Mr = 201.23, monoclinic, P2i/c, a = 9.5350(9), b = 14.310(2), c= 7.4961 (8) A, B = 105.280(1)°, V = 986.7 (4) A3, Z= 4, Dx = 1.355 Mgrn~(-3), X(MoKa) = 0.71073 A, n = 0.085 mm~(-1), F(000) = 424, 7 = 160 K, R = 0.047 for 1732 reflections. There is a broad range of molecular conformations for these bipyridines, as reflected by the bipyridine torsion angle C(2)-C(l)-C(l')-C(2'). The largest angles are observed for the two 2'-methyl milrinone analogues (I) and (II), which have values of 144.2(2) and 74.3(2)°, respectively, compared with that of 42.3° observed for milrinone. The addition of either a 2- or 2'-methyl to amrinone causes the almost coplanar parent structure to adopt twist angles of 38.5(2) and -36.8(2)° for molecules 1 and 2 of (HI), respectively, and 59.4(3)° for (IV). A common feature of these structures is a hypercentric distribution of their normalized structure factors. Ring-ring stacking interactions observed in these structures contribute to the hyperparallelism observed in some crystal lattices or the creation of superlattices by the addition of noncrystallographic symmetry in other structures. These bipyridine molecules form a network of hydrogen bonds with the keto O or pyridine N atoms acting as acceptors and the pyridone 3-N or 5-amino group acting as donors. Each of the two independent bipyridinium cations of (III) form alternate layers in the lattice and are involved in a two-dimensional network of hydrogen bonds. Biochemical activity, as measured by the stimulatory effect on rabbit myocardial membrane Ca2+-ATPase activity, reveals that only (II) and (HI) have appreciable activity with 49 and 57% of enzyme stimulation by milrinone, respectively.