MK 0633, SETILEUTON
910656-27-8 CAS free form
MW 463.3817, C22 H17 F4 N3 O4 FREE FORM
Tosylate cas 1137737-87-1
|Inventors||Thiadiazole substituted coumarin derivatives and their use as leukotriene biosynthesis inhibitor
WO 2006099735 A1Marc Blouin, Erich L. Grimm, Yves Gareau, Marc Gagnon, Helene Juteau, Sebastien Laliberte, Bruce Mackay, Richard Friesen,
|Applicant||Merck Frosst Canada Ltd.|
MK-0633 had been in early clinical development for several indications, including the treatment of chronic obstructive pulmonary disease (COPD), asthma and atherosclerosis
Leukotriene metabolism plays a central role in inflammatory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and atherosclerosis. In particular, the activation of the enzyme 5-lipoxygenase (5-LO) and its associated protein, 5-LO activating protein (FLAP), initiates a cascade that transforms arachidonic acid into inflammatory leukotrienes
Inhibition of leukotriene biosynthesis has been an active area of pharmaceutical research for many years. The leukotrienes constitute a group of locally acting hormones, produced in living systems from arachidonic acid. Leukotrienes are potent contractile and inflammatory mediators deπved by enzymatic oxygenation of arachidonic acid by 5-hρoxygenase. One class of leukotriene biosynthesis inhibitors are those known to act through inhibition of 5 -lipoxygenase (5-LO).
The major leukotrienes are Leukotriene B4 (abbreviated as LTB4), LTC4, LTD4 and LTE4. The biosynthesis of these leukotrienes begins with the action of the enzyme 5-lipoxygenases on arachidonic acid to produce the epoxide known as Leukotriene A4 (LT A4), which is converted to the other leukotπenes by subsequent enzymatic steps. Further details of the biosynthesis as well as the metabolism of the leukotπenes are to be found in the book Leukotrienes and Lipoxygenases, ed. J. Rokach, Elsevier, Amsterdam (1989). The actions of the leukotπenes in living systems and their contπbution to various diseases states are also discussed in the book by Rokach.
In general, 5 -LO inhibitors have been sought for the treatment of allergic rhinitis, asthma and inflammatory conditions including arthπtis. One example of a 5-LO inhibitor is the marketed drug zileuton (ZYLOFT®) which is indicated for the treatment of asthma. More recently, it has been reported that 5-LO may be an important contributor to the atherogenic process; see Mehrabian, M. et al., Circulation Research, 2002 JuI 26, 91(2): 120-126.
Despite significant therapeutic advances in the treatment and prevention of conditions affected by 5-LO inhibition, further treatment options are needed. The instant invention addresses that need by providing novel 5-LO inhibitors which are useful for inhibiting leukotriene biosynthesis.
Synthesis of coumarin intermediate in MK-0633. Reagents and conditions: a) 2.7 M H2SO4 (1 mL/1 mmol), 1.1 equiv. NaNO2, –5 °C, 15 min, 1.5 equiv. KI (1 M H2SO4, 1 mL/0.5 mmol), 0–70 °C, 20 min; b) 1.5 equiv. CuCN, DMF, 110 °C, 24 h, 72 % (over two steps); c) 0.05 equiv. H2SO4, MeOH, 60 °C, 12 h, 81 %; d) 2.5 equiv. 2 M AlMe3, 1.5 equiv. NH(OMe)Me·HCl, THF, room temp., 24 h, 86 %; e) 4.0 equiv. C6H4FMgBr, THF, 0 °C to room temp., 3 h, 74 %; f) toluene, reflux, 24 h, 83 %.
Synthesis of a 5-Lipoxygenase Inhibitor
Practical, chromatography-free syntheses of 5-lipoxygenase inhibitor MK-0633 p-toluenesulfonate (1) are described. The first route used an asymmetric zincate addition to ethyl 2,2,2-trifluoropyruvate followed by 1,3,4-oxadiazole formation and reductive amination as key steps. An improved second route features an inexpensive diastereomeric salt resolution of vinyl hydroxy-acid 22 followed by a robust end-game featuring a through-process hydrazide acylation/1,3,4-oxadiazole ring closure/salt formation sequence to afford MK-0633 p-toluenesulfonate (1).
|Patent ID||Patent Title||Submitted Date||Granted Date|
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