Acidic epinephrine analogues derived from 1H, 3H-2,1,3-benzothiadiazole 2,2-dioxide and from trifluoromethanesulfonanilide. A new synthesis of 1H,3H-2,1,3-benzothiadiazole 2,2-dioxide.

Treatment of N,N'-dibenzyl-1,2-diaminobenzene (2) successively with thionyl chloride and then m-chloroperbenzoic acid gave N,N'-dibenzyl-1H,3H-2,1,3-benzothiadiazole 2,2-dioxide (4), which gave (via routes analogous to standard epinephrine syntheses) four bicyclic catecholamine analogues 7a-d. Hydrogenolysis of 4 yielded the parent heterocycle 5 in the first practicable synthesis avoiding expensive sulfamide (Scheme I). The trifluoromethanesulfonamidoacetophenones 8m and 8p on similar elaboration gave triflanilide catecholamine analogues 14m, 14p,17m, and 17p (Scheme II). 4,4'Dimethoxybenzhydrylamine (15) is recommended for the regiospecific synthesis of primary amines from epoxides (Scheme II). Series 7,14, and 17 were inactive in animal cardiovascular screens. Selected compounds were also screened in bronchodilator and in in vitro dopamine-, clonidine-, and prazosin-receptor binding assays as appropriate; again no activity was observed. Steric lipophilicity, and acidity factors are discussed, and the inactivity is ascribed to the high acidity of both systems (pKa approximately equal to 4).

The definition and identification of need for health care.

Some definitions of need for health care as a basis of planning health services are discussed. A model proposed by Donabedian (1974) relating need to resources is used to consider the problems faced by the Resource Allocation Working Party (RAWP) (Department of Health and Social Security, 1976). The paper concludes that need should be defined in relation to the procedures available to meet it and the resources that permit those procedures to be used. The procedures include the whole gamut of prevention and screening, cure and care, research and development. This necessarily raises moral and ethical issues which stretch beyond the limits of medicine and concern patients, their relatives, and the public in general. Neither the medical profession nor the lay public can be expected to help define need for health care unless they understand the underlying issues. This is a challenge to those responsible for professional and public education.

Experimental DNA-binding and computer modelling studies on an analogue of the anti-tumor drug amsacrine.

The DNA-binding properties of the anti-cancer drug amsacrine and a 9-aminoacridine analogue substituted at the 4 position with a 4-methanesulphonanilido-group, have been examined by means of unwinding, melting and equilibrium binding experiments. These find that the latter compound is at least as effective as a DNA-binder and intercalator as amsacrine itself. Molecular modelling and energetic calculations have confirmed this, and have produced plausible intercalation geometries. These show that there are subtle differences in the low-energy minor groove arrangements adopted by the substituents of the two drugs. Speculation is advanced that these differences may be relevant to the marked differences in cytotoxicity shown by the two compounds.