Arachidonic acid is a fatty acid that is essential in the body and is stored in cell membranes. It may be converted, e.g. in the event of inflammation, into mediators, some of which are known to have beneficial properties, such as the lipoxins and resolvins and others that are harmful. Such mediators include leukotrienes (formed by the action of 5-lipoxygenase (5-LO), which act by catalysing the insertion of molecular oxygen into carbon position 5 of arachidonic acid generating 5-hydroxyeicosatetraenoic acid and then LTA4), prostaglandins (which are formed by the action of cyclooxygenases (COXs)) and eoxins (formed by the action of 15-lipoxygenase (15-LO), which act by catalysing the insertion of molecular oxygen into carbon position 15), followed by conjugation with glutathione catalysed by leukotriene C4 synthase. Huge efforts have been devoted towards the development of drugs that inhibit the action of some of these metabolites as well as the biological processes that form them.
Of the leukotrienes, leukotriene (LT)B4 is formed by the action of 5-lipoxygenase and leukotriene A4 hydrolase. LTB4 is known to be involved in neutrophil recruitment and may play an important role in host defence. The cysteinyl-containing leukotrienes C4, D4 and E4 (CysLTs), formed by the action of 5-lipoxygenase and cysteine leukotriene C4 synthase, are both very potent bronchoconstrictors and proinflammatory mediators and have thus been implicated in the pathobiology of asthma. The biological activities of the CysLTs are mediated through two receptors designated CysLT1, which is the preferred receptor for LTD4, and CysLT2, which is the preferred receptor for LTC4, but the existence of additional CysLT receptors, such as CysLT3, a receptor with preference for LTE4, has also been proposed. Leukotriene receptor antagonists (LTRAs) have been developed for the treatment of asthma, but they are often highly selective for CysLT1. It may be hypothesised that better control of asthma may be attained if the activity of all the leukotrienes at CysLT receptors could be reduced. This may be achieved by developing unselective LTRAs, but also by inhibiting the activity of proteins, e.g. enzymes, involved in the synthesis of the CysLTs; 5-LO, 5-lipoxygenase-activating protein (FLAP), and leukotriene C4 synthase may be mentioned. However, 5-LO inhibitors and/or FLAP inhibitors would also decrease the formation of LTB4, and pro-resolution lipids lipoxins and resolvins. In addition to inhibiting the synthesis of CysLTs, inhibition of leukotriene C4 synthase will inhibit the formation of eoxins that are known proinflammatory mediators, while preserving anti-inflammatory lipids such as the lipoxins. For a review on leukotrienes in asthma, see e.g., H.-E. Claesson and S.-E. Dahlén J. Internal Med. 245, 205 (1999). For a review on eoxins in asthma, see e.g., H.-E. Claesson Prostaglandins Other Lipid Mediat. 89, 120-125 (2009).
There are many diseases/disorders that are inflammatory in their nature or have an inflammatory component. One of the major problems associated with existing treatments of inflammatory conditions is a lack of efficacy and/or the prevalence of side effects (real or perceived).
Asthma is a chronic inflammatory disease affecting 6% to 8% of the adult population of the industrialized world. In children, the incidence is even higher, being close to 10% in most countries. Asthma is the most common cause of hospitalization for children under the age of fifteen.
Treatment regimens for asthma depend upon the severity of the condition. Mild cases are either untreated or are only treated with inhaled (3-agonists. Patients with more severe asthma are typically treated with anti-inflammatory compounds on a regular basis.
There is a considerable under-treatment of asthma, which is due at least in part to perceived risks with existing maintenance therapy (mainly inhaled corticosteroids). These include risks of growth retardation in children and loss of bone mineral density, resulting in unnecessary morbidity and mortality. As an alternative to steroids, LTRAs have been developed. These drugs may be given orally, but are considerably less efficacious than inhaled steroids and usually do not control airway inflammation satisfactorily. This combination of factors has led to at least 50% of all asthma patients being inadequately treated.
A similar pattern of under-treatment exists in relation to allergic disorders, where drugs are available to treat a number of common conditions but are underused in view of apparent side effects. For instance, rhinitis, conjunctivitis and dermatitis may have an allergic component, but may also arise in the absence of underlying allergy. Indeed, non-allergic conditions of this class are in many cases more difficult to treat.
Other inflammatory disorders which may be mentioned include: chronic obstructive pulmonary disease (COPD) is a common disease affecting 6% to 8% of the world population. The disease is potentially lethal, and the morbidity and mortality from the condition is considerable. At present, there is no known pharmacological treatment capable of changing the course of COPD; pulmonary fibrosis (this is less common than COPD, but is a serious disorder with a very poor prognosis); inflammatory bowel disease (a group of disorders with a high morbidity rate—today only symptomatic treatment of such disorders is available); rheumatoid arthritis and osteoarthritis (common disabling inflammatory disorders of the joints—there are currently no curative, and only moderately effective symptomatic, treatments available for the management of such conditions); diabetes, a disease affecting over 3% of the world population, and growing, causing considerable morbidity and mortality; and cardiovascular disease.
Inflammation is also a common cause of pain. Inflammatory pain may arise for numerous reasons, such as infection, surgery or other trauma. Moreover, several malignancies have inflammatory components adding to the symptomatology of the patients. Inflammation may also play a role in cancer with leukotrienes involved in cancer cell proliferation and extending cancer cell lifetimes.
Thus, new and/or alternative treatments for respiratory and/or inflammatory disorders would be of benefit to all of the above-mentioned patient groups. In particular, there is a real and substantial unmet clinical need for an effective anti-inflammatory drug capable of treating inflammatory disorders, in particular asthma, with no real or perceived side effects.
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
International patent publications WO 2009/030887, WO 2010/103297, WO 2010/103278, WO 2010/103279, WO 2010/103283 and WO 2011/110824 disclose bis-aromatic ketones thought to be LTC4 synthase inhibitors and their potential use in the treatment of respiratory and/or inflammatory diseases. These disclosures contain no teaching or suggestion relating to the use of cyclopropyl-substituted aryl and heteroaryl ketones.