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.

The antiallergic activity of some xanthone derivatives containing a sulfoximide substitutent has been investigated. While 2-(S-methylsulfonimidoyl)xanthone itself was found to be inactive, a series of 7-(S-methylsulfonimidoly)-xanthone-2-carboxylic acids showed good levels of activity in the passive cutaneous anaphylaxis screen. N-Substituted sulfoximide derivatives were, without exception, less active than the corresponding unsubstituted compounds. The activity of the 7-(S-methylsulfonimidoyl)xanthone-2-carboxylic acids could be enhanced by the introduction of an alkyl or alkoxy substituent at C-5. As a result of these studies, 5-hexyl-7(S-methylsulfonimidoyl)xanthone-2-carboxylic acid has been selected for further investigation as an antipasthmatic agent.

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Various cyclocondensation reactions, yielding the heterocyclic systems mentioned in the title, are described.