Sulfamide HIV-1 protease inhibitors

An expeditious route to the cyclic sulfamide HIV-1 protease inhibitors of type 145 and 146 (tetrahydro-l,2,7-thiadiazepine 1,1-dioxide derivatives) from 141 and 142 hinges on palladium-catalysed amidation reactions. These reactions of 144 and 143 were microwave promoted and provided, after removal of the cyclic ketal protecting group, moderate to good yields of (145, 57%) and (146, 66%) for example with R = NHCOCH2-2-naphthyl <06T4671>. 

Scheme 18 Optimization of cyclic sulfamide HIV-1 protease inhibitors...

In a 2006 paper outlining the rapid microwave synthesis of novel cyclic sulfamide HIV-1 protease inhibitors, the aminocarbonylation protocol presented in ref. 17 was applied in the decoration of mono- and bis-aryl bromide containing cyclic sulfamide starting materials [33]. Aniline and benzylamine were used as nucleophiles for the production of two symmetric bis-functionalized and two unsymmetrical monosub-stituted compounds in good yields (59-80%) (Scheme 4.19). Unfortunately, of these anilide or benzylamide containing compounds only one displayed weak HIV-1 protease inhibition [33]. 

Gold, H., Ax, A., Vrang, L, Samuelsson, B Karlen, A., HaUberg, A. and Larhed, M. (2006) Fast and selective synthesis of novel cyclic sulfamide HIV-1 protease inhibitors imder controlled microwave heating. Tetrahedron, 62, 4671—4675. 

Other types of HIV-1 protease inhibitors have also been prepared using microwave-promoted Suzuki reaction [37]. The symmetric cyclic sulfamide (3K,4S,5S,6it)-3,6-bis(phenoxymethyl)-2,7-bis[4-(2-thienyl)benzyl]-l,2,7-thi-adiazepane-4,5-diol 1,1-dioxide, for instance, was synthesized via cross-couphng of (3aS,4R,8it,8aS) - 5,7 - bis(4 - bromobenzyl) - 2,2 - dimethyl - 4,8 - bis-(phenoxymethyl) hexahydro [1,3] dioxolo [4,5 - d] [ 1,2,7 ] - thiadiazepine 6,6 - dioxide with 2-thienylboronic acid for 3 min at 45 W (Scheme 19). 

Unsaturated 1,1-dioxo derivatives 30 were accessed in c. 60% yields via cyclization of mannitol derivatives 29 with sulfamide in pyridine <1997JME885, 1999JME4054, 2001JME155, 2002OL4673>. As a part of a medicinal chemistry approach to HIV-1 protease inhibitors, the resulting products 30 were further alkylated with benzyl bromide in >90% yields (Scheme 3). 

A class of HIV-l protease inhibitors extensively examined in our department are the cyclic sulfamides [73,74]. These compounds are related to our linear 1,2-dihydroxyethylene inhibitors described above in that they are also derived from L-mannitol and employ a 1,2-dihydroxyethylene transition-state isostere. These cyclic inhibitors are comprised of seven-membered rings where the sulfonyl oxygens are designed to displace a structural water in the enzyme when the inhibitors bind to the active site [73]. The synthesis of the... 

Hulten, J., Andersson, H.O., Schaal, W. et al. (1999) Inhibitors of the C(2)-symmetric HIV-1 protease nonsymmetric binding of a symmetric cyclic sulfamide with ketoxime groups in the P2/P2 side chains. J. Med. Chem., 42, 4054-61. 

Many other non-peptide inhibitors of HIV protease (dihydropyrone, cyclic urea and sulfamide series of compounds) were obtained by modifications of random screening leads. Examples of these include a cyclic sulfone derivative (133) and PNU-140690 (134), which showed activity against a variety of laboratory strains of HIV-1, clinical isolates and other variants resistant to other protease inhibitors. 

---