The novel 1,4-naphthalenediol and 1,4-hydroquinone compounds of the present invention are 5-lipoxygenase and leukotriene inhibitors and as such are useful for treating diseases that result in bronchial constriction such as bronchial asthma, bronchitis, bronchiectasis. pneumonia and emphysema. Some of the compounds of this invention also exhibit varying degrees of thromboxane A.sub.2 synthetase inhibiting activity and/or cyclooxygenase inhibiting activity as well. For many of the intended applications, such as asthma, bronchitis, bronchiectasis, pneumonia and emphysema, the combination of the three inhibiting effects may be desirable for some of the intended applications.
The leukotrienes are a class of unsaturated fatty acid compounds which are derived from arachidonic acid by the action of lipoxygenase See, e.g., Samuelsson, Trends in Pharmacological Sciences, 5:227 (1980); and Samuelsson, et al., Annu. Rev. Biochem. 47:997-1029 (1978). For a discussion of leukotriene nomenclature, see Samuelsson, et al., Prostaglandins, 19:645 (1980).
The leukotrienes have been found to be potent constrictors of human bronchi. That is, certain leukotrienes are mediators of the action of slow-reacting substance of anaphylaxis (SRS-A). See, e.g., Dhalen, Nature, 288:484 (1980). These compounds are therefore important mediators of bronchoconstriction in humans.
The role of leukotrienes as agonists in immediate hypersensitivity and other pathological conditions has led to research into leukotriene antagonists and inhibitors of leukotriene biosynthesis. See, e.g., Corey, et al., Tet. Lett. 21:4243 (1980).
Leukotrienes, particularly leukotriene C.sub.4 (LTC.sub.4) and leukotriene D.sub.4 (LTD.sub.4) have been shown to be potent mucus secretagogues. Mucus secreted from submucosal glands and surfaces at the epithelial cells combines with water to form part of the respiratory tract secretions. In healthy states mucus secretion in the respiratory tract is about 50 to 150 ml per day in man. The excessive production of mucus, however, is an important feature of many pulmonary diseases. For example, in chronic bronchitis the flow of mucus increases up to fourfold. The lack of the ability of the patient to deal with this hyper-production leads to pathological conditions of the airways such as chronic bronchitis, asthma, and cystic fibrosis where there is a defect in consistency or clearance of the mucus. Therefore it is medically desirable to regulate the hypersecretion of mucus (J. G. Widdicobe, Brit. Med. Bull. 34, 57-31 (1978)). Historically attempts have been made to treat the symptoms without regulation of the root cause. For example, mucolytics, acetylcysteine containing solutions, as well as iodides have been used. Also, antibiotics are used to treat infections in cystic fibrosis because no known drug can regulate the consistency of the mucus in this disease condition. Both LTC.sub.4 and LTD.sub.4 increase the release of mucus from human airways in vitro, Z. Maron, et al., Am. Rev. Respir. Dis. 126, 449-451 (1982); S. J. Coles, et al., Prostaglandins 25, 155-170 (1983), and from canine tracheas in vivo, H. G. Johnson, et al., Int. J. Immunopharmacol. 5, 178 (1983); H. G. Johnson, et al., Prostaglandins 25, 237-243 (1983). Arachidonic acid, metabolic products or arachidonic acid, monohydroxy-eicosatetraenoic acid, and prostaglandins also release mucus from human airways, Z. Maron, et al., J. Clin. Invest. 67, 1695-1702 (1981). LTC.sub.4 was effective in stimulating mucus release in vivo in the cat but not in vitro in cat trachea tissue, A. C. Peatfield, et al., Br. J. Pharmac. 77, 391-393 (1982). J. H. Shelhamer, et al., Chest. 81, 36s (1982) summarizes the nature of evidence available suggesting that lipoxygenase products generated by the airways in vitro might be responsible for the augmented mucus release.
O. Cromwell, et al., The Lancet, July 25, 1981, pp. 164-165, identified LTB.sub.4 and LTD.sub.4 in the sputum of cystic fibrosis patients and speculated, therefore, that inhibitors of the lipoxygenase pathway might be capable of reversing the airway obstruction in such patients.
T. Ahmed, et al., Am. Rev. Respir. Dis. 124, 110-114 (1981) demonstrated FPL 55712, an LTC.sub.4 antagonist when given prior to antigen challenge was effective in reversing the tracheal mucus velocity in patients with a history of bronchial asthma but concluded that the clinical significance of FPL 55712 remains to be demonstrated.
In mammalian metabolism, arachidonic acid is transformed to 12-L-hydroperoxy-5,8,10,14-eicosatetraenoic acid by the action of 12-lipoxy-genase. See, Hamberg, et al., Proc. Nat. Acad. Sci. 71:3400-3404 (1974). Similarly, 5-lipoxygenase transforms arachidonic acid into 5-S-hydroperoxy-6,8,11,14-eicosatetraenoic acid. Thus, an agent which inhibits the action of lipoxygenase would be useful in treating or preventing untoward conditions associated with lipoxygenase products.
Therefore, compounds which inhibit the action of lipoxygenase are useful in the treatment of inflammatory conditions where it is desirable to prevent migration of polymorphonuclear leukocytes to the inflammatory site. They are also useful in the treatment of asthma.
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