QSAR and CoMFA Study of Cocaine Analogs: Crystal and Molecular Structure of (–)-Cocaine Hydrochloride and N-Methyl-3β-(p-Fluorophenyl)Tropane-2β-Carboxylic Acid Methyl Ester

A QSAR and CoMFA study including 78 cocaine analogs has been completed. These analogs have varied functional groups on the 2 and 3 positions of the tropane ring and include various stereoisomers. The CoMFA program was used to calculate the steric and electrostatic interaction energies as a probe atom or probe charge interacts with the molecules. Shaded contour maps show regions of the cocaine analogs where an increase in bulky substituents is desirable for increased pharmacological activity. The maps also show that small electronegative substituents on the phenyl ring are favored for enhanced activity. The X-ray crystal structures of (–)-cocaine hydrochloride (1) and N-methyl-3-(p-fluorophenyl)tropane-2-carboxylic acid methyl ester (2) are reported. These molecules are mostly rigid except for some rotational flexibility in the orientation of the phenyl and benzoyl functional groups. Crystallographic data: (1) C₁₇H₂₁NO₄·HCl, orthorhombic space group P2₁2₁2₁, a = 7.622(1)Å, b = 10.285(1)Å, c = 21.428(3)Å, Z = 4, final R = 0.035 for 960 observed reflections (I>3(I)). (2) C₁₆H₂₀FNO₂, monoclinic space group C2, a = 22.572(7)Å, b = 5.810(1)Å, c = 15.752(4)Å, = 133.65(2)°, Z = 4, final R = 0.059 for 1511 observed reflections (I>3(I)).     

Synthesis and stereochemical assignment of exo- and endo-7-methyl-7-azabicyclo[2.2.1]heptan-2-ol

[formula: see text] The syntheses of both exo and endo stereoisomers of 7-methyl-7-azabicyclo[2.2.1]heptan-2-ol were achieved in straightforward fashion. Alternatively, the intramolecular cyclization of syn-4-N-methylaminocyclohexane 1,2-epoxide was found to give exo-7-methyl-7-azabicyclo-[2.2.1]heptan-2-ol as the sole product. The stereochemistry of the exo isomer was unequivocally confirmed by X-ray crystallography.     

A Crystallographic Investigation of Ergolines

The X-ray crystal structures of three ergoline derivatives have been completed and are reported herein. These include mesulergine hydrochloride (III), pergolide methanesulfonate (IV), and dihydroergocriptine hydrate (V). These molecules show dopamine agonist activity at the D2 receptor. These three-dimensional structures were compared to structurally similar molecules with similar pharmacological activity. It was found that ergoline derivatives have rigid fused-ring systems with substituents that can exist in a variety of conformations. The ergoline structures reported here have structural features consistent with other active dopamine agonists. Crystallographic data: (III) C₁₈H₂₆N₄O₂S HCl, monoclinic space group P2₁, a = 12.183(2) Å, b = 6.174(2) Å, c = 13.649(2) Å, = 105.55(1)°, Z = 2, final R = 0.071 for 2293 observed reflections [I > 3(I)]; (IV) C₁₉H₂₇N₂S CH₃SO₃, mono- clinic space group P2₁, a = 8.455(4) Å, b = 29.868(4) Å, c = 8.957(6) Å, = 111.95(5)°, Z = 4, final R = 0.055 for 3836 observed reflections; (V) C₃₂H₄₃N₅O₅ H₂O, monoclinic space group P2₁, a = 12.403(2) Å, b = 18.103(3) Å, c = 15.418(3) Å, = 113.04(2)°, Z = 4, final R = 0.058 for 3208 observed reflections.