Crystal and molecular structure of the histamine H2-receptor antagonists, N-methyl-N′-{2-[(5-methylimidazol-4-yl)methylthio]ethyl}thiourea (metiamide) and N-{2-[(imidazol-4-yl)methylthio]ethyl}-N′-methylthiourea (thiaburimamide)
Abstract
The crystal and molecular structures of the title compounds have been determined from three-dimensional X-ray diffractometer data by direct methods. Metiamide (Ia) is monoclinic, P21/n(b unique), Z= 4, a= 10.229 ± 0.008, b= 19.045 ± 0.009, c= 6.701 ± 0.003 Å, β= 107.76°± 0.004. Thiaburimamide (Ic) is also monoclinic, space goup P21/c(b unique)Z= 4, a= 9.981 ± 0.003, b= 5.928 ± 0.003, c= 20.396 ± 0.007 Å, β= 105.36 ± 0.02°. Data were refined by least-squares to R= 4.4% in both cases (2 226 and 2 903 independent reflections). Both molecules are internally hydrogen bonded by an N ⋯ H–N bond between the imidazole and thiourea residues, forming a ten-membered ring system. These molecules are further agglomerated in continuous hydrogen-bonded networks. In (Ic) the molecules are linked in pairs by S ⋯ H–N bonds and further into infinite ribbons parallel to c. (Ia) is similarly involved in a complex hydrogen-bonding pattern, to form sheets. These differences are reflected in the relative crystal stabilities, as judged from m.p.s and aqueous solubilities. The compounds are compared with those having CH2 in place of the thioether S linkage, viz. burimamide (Ib) and its 5-methyl derivative (Id). Solid-state i.r. spectra indicate that (Id), like (Ib) does not form the intramolecular hydrogen-bond in the crystal. Thus it appears that the thioether linkage may increase conformational flexibility and favour folding of the side-chain; these effects may contribute to the increased activity of the title compounds as histamine H2-receptor antagonists.