PDE-IV inhibitors

Furthermore, it was recently shown, that enantiopure diaryl methanols can undergo stereospecific SN2-type substitution reactions with enolates at the (di)benzylic carbon affording 1,1-diarylalkyl derivatives (31 — 32 —> 33 Scheme 2.1.2.4). This discovery widened the preparative applicability of diaryl methanols significantly, and was used by Merck in the synthesis of selective PDE-IV inhibitors 34 and 35 [32]. 

J.E. Lynch and co-workers reported the asymmetric total synthesis of the PDE IV inhibitor CDP840 in which they utilized the Jacobsen epoxidation to introduce the only stereocenter of the target. The triaryl (Z)-olefin substrate was epoxidized with significantly higher enantiomeric excess than the triaryl ( )-olefin. This finding was interpreted with Jacobsen s skewed side-on approach model. 

Chemistry conceptually similar to that described for tamoxifen analogs 218 has been applied to the synthesis of CDP840 222, a phosphodiesterase (PDE) IV inhibitor for the treatment of asthma [78]. In combination with the Liebeskind-variation of the Suzuki reaction, thiopyrimidine ether 220 was cross-coupled to pyridyl-4-boronic acid 210 to afford 221. Catalytic hydrogenation of the olefin gave rise to 222. 

PDE IV inhibitors [79]. The highly elaborated intermediate 223 was coupled with the... 

The principal asthma therapies have all been in clinical practice since the early 1970s and before, yet their mechanisms and potential hazards in many cases remain obscure. The trend towards inhaled corticosteroids continues to raise concerns about their long-term side-effects. This has fuelled efforts to develop safer anti-inflammatory therapies, despite the advent of fluticasone, which is 100 per cent first-pass metabolized in the liver and has fewer systemic effects (Harding, 1990). Suggestions that the long-actingy 2-agonists (salmeterol, formoterol) may be anti-inflammatory appear to be unfounded, but the possibility of an antiinflammatory effect of theophylline (Ward et al., 1993) has accelerated development of selective phosphodiesterase (PDE IV) inhibitors, which may have reduced side-effects and a better therapeutic index than theophylline itself. The immunosuppressants, such as cyclosporin A which prevents expression of IL-2 and IL-2R in T cells, are limited by toxicity to a small minority of very severe corticosteroid-dependent asthmatics. 

PDE IV inhibitors, as well as some combined PDE IIl/IV inhibitors, are currently under development for the treatment of asthma (Christensen and Torphy, 1994 Nicholson and Shahid, 1994). The basis for this development includes bronchodilatory activity directly related to inhibition of PDE IV, and/or PDE III, in airway smooth muscle, as well as the antiinflammatory activity of these compounds. PDE IV is the major cAMP PDE isozyme present in inflammatory cell types and inhibition of PDE IV has been linked to elevation of cAMP and inhibition of histamine or leukotriene release from mast cells, inhibition of oxygen free radical release from eosinophils or neutrophils, inhibition of adhesion, migration, or activation of eosinophils, and inhibition of TNF-a release from human monocytes (see Nicholson and Shahid, 1994, or Christensen and Torphy, 1994, for some reviews). There are now known to be at least four sub-types of PDE IV that are encoded by different cDNAs (Bolger et al., 1993 Davis et al, 1989 Livi et al., 1990). Although sequence homology of 75-90% is evident among subtypes, key differences, as well as cellular distribution, are apparent. Currently there are no selective inhibitors of the PDE IV subtypes. 

Among the combined PDE III/IV inhibitors are zar-daverine. The basis for these compounds includes better bronchodilation (relative to PDE IV inhibitors) and lower cardiovascular effects (relative to PDE III inhibitors). 

The key step in the synthesis of CDP840 ( 108), a phosphodiesterase IV (PDE IV) inhibitor for the treatment of asthma included the Liebeskind variation of the Suzuki reaction i.e., the thiopyrimidine ether 106 was cross-coupled with pyridyl-4-boronic acid to afford 107. Catalytic hydrogenation of 107 then afforded racemic 108. 

Scheme 9.17 Domino reductive ring-opening/double cyclization synthesis of phosphodiesterase (PDE) IV inhibitor.

Scheme 32 Synthesis of PDE IV inhibitor through y-selective addition of y-butyrolactam...

Conjugate addition of the y-butyrolactam to enals was promoted by diphenyl-prolinol trimethylsilyl ether 12 via the iminium activation process (Scheme 32, second hne) [53]. A satisfactory level of enantioselectivity was generally observed irrespective of the solvent polarity, although the use of aqueous acetonitrile was superior for optimizing the chemical yield and enantioselectivity. In addition, acidic additives had apparent effects on the reaction profile and the highest diastereoselectivity was attained with 2-fluorobenzoic acid. The synthetic utility of this site- and stereoselective transformation was demonstrated in a series of product derivatizations, including the three-step synthesis of a cAMP-specific phosphodiesterase (PDE IV) inhibitor (Scheme 32, third hne). 

The imidazo[l,2-a]quinoxaline derivatives are cyclic nucleotide phosphodiesterase type in (PDE-111) and type IV (PDE-IV) inhibitors with promising activity in case of 4-(methylamino)imidazo[l,2-brain uptake and high selectivity for both PDE-II and PDE-X enzymes [8b] (Fig. 2.4). 

The phosphodiesterase (PDE) IV inhibitor (109, Scheme 2.17) has been identified by Merck Research Laboratories as a potential lead for the treatment of asthma. Although an early synthesis of 109 relied on the use of Oppolzer s chiral sultam auxiliary, a more economic approach was subsequently developed that exploited an aminoindanol auxiliary. In the revised synthesis, the car-boxyhc acid 103 (available in two steps from isovanillin) is coupled with (15,2/ )-cis -aminoindanol 12 and subsequently converted into the amide 104. After protection of the amino alcohol, reaction of the resulting Michael acceptor 106 with phenyllithium 107 and subsequent... 

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