The active metabolite (2) of the novel immunosuppressive agent leflunomide (1) has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. A series of analogues of the active metabolite 2 have been synthesized. Their in vivo biological activity determined in rat and mouse delayed type hypersensitivity has been found to correlate well with their in vitro DHODH potency. The most promising compound (3) has shown activity in rat and mouse collagen (II)-induced arthritis models (ED50 = 2 and 31 mg/kg, respectively) and has shown a shorter half-life in man when compared with leflunomide. Clinical studies in rheumatoid arthritis are in progress.

4H-Imidazo[2,1-c][1,4]benzoxazine-2-carboxylic acid (3) was found to possess potent activity in the IgE-induced rat passive cutaneous anaphylaxis model which may be predictive of clinical antiallergic activity. Compared to disodium cromoglycate (DSCG, 1), 3 was less active following iv administration but unlike DSCG showed very significant oral activity. To explore the structural requirements for this activity, a range of tricyclic compounds was prepared and their activities were measured. Individual 2-carboxylic acids derived from imidazo[1,2-a]quinolines, imidazo[1,2-a]quinoxalines, imidazo[1,2-a]quinoxalinones, pyrrolo[1,2-a]quinoxalinones, pyrrolo[2,3-a]quinoxalinones, and imidazo[2,1-b]benzothiazoles showed iv activities up to 10(3) times as potent as DSCG and many of them showed significant oral activity. From these, imidazo[1,2-a]quinoxaline-2-carboxylic acid 114 has been chosen for further development.

A number of derivatives of 2-methyl-3-(o-tolyl)-4(3H)-quinazolone bearing new substituents on the 2-methyl group have been synthesized. It was established that most substitutions at this position reduce or remove the CNS depressant activity of methaqualone. From the series prepared only the 2-fluoromethyl derivative or certain isothiouronium salts, which could be hydrolyzed in vivo to the 2-mercaptomethyl derivative, showed activity of the same magnitude as methaqualone.

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A detailed study has been made of the effects of substituents, X, upon the shielding of lgF nuclei in series of meta and para-X-fluorobenzenes, 4-X-4'-fluoro-trans-stilbenes, and 3'-fluoro-4-X-trans-stilbenes. The correlation of substituent chemical shifts for lSF nuclei in fluoroaromatic compounds with reactivity parameters is examined, and a reassessment is made of the Taft and Swain and Lupton separation of polar substituent effects into field/inductive and resonance components. Science and Technology, London SW7 2AYTHE study of substituent effects upon 19F shielding in aromatic fluorine-containing molecules is of interest .1-3 Many attempts have been made to interpret such effects in terms of local electron density changes caused by the ring substituents, by use of a variety of molecular orbital methods ranging from the simple Huckel MO theory to VESCF method^.^ The approach underlying most of this work has been to assume that in para-substituted fluorobenzenes the interacting groups are sufficiently separated for o bond effects to be negligible and to relate the observed shielding changes to x-electronic density variation upon the carbon atom a t o fluorine. A growing amount of experimental evidence t Part I, I. R. hger and L. Phillips, preceding paper.