Ureas, cyclic

Flow chart showing the design of novel orally active HIV-1 protease inhibitor. (Figure adapted from Lam P K ]adhav, C E Eyermann, C N Hodge, Y Ru, L T Bacheler, ] L Meek, M ] Otto, M M Rayner, Y N V /ong, ang, P C Weber, D A Jackson, T R Sharpe and S Erickson-Viitanen 1994. Rational Design of Potent, able. Nonpeptide Cyclic Ureas as HIV Protease Inhibitors. Science 263 380-384.)... 

The thio analogs are similarly prepared by using carbon disulfide instead of phosgene. These compounds react as cyclic ureas and thioureas. 

Amino- and hydrazino-quinazolines exhibited antibacterial ac-tivity and a patent claim on the in vitro action of 2,4-diamino-quinazolines was rnade. The preparation of thiopegan derivatives as potential antimalarials and antibacterials deserves mention. Complete inhibition of influenza virus in vitro but not in vivo was shown by. 6,8-dichloro-2,4-dihydroxyquinazoline and other cyclic ureas. Activity against trachoma virus was also displayed by several 2-trichloromethylquinazolines. ... 

One of the more interesting reactions involving the reduction of a sulphone was recently described in a paper87 that reported on a synthetic approach to biotin. The molecule in question contains a sulphone as part of a thiolane ring that is fused to a cyclic urea. As outlined in equation (33), either functionality can be reduced depending on the selection of... 

Cyclic ureas can be obtained by reaction of simple urea with 1,2-diamino derivatives in DMF in the presence of ZnO and under microwave irradiation (Scheme 53). In this unusual condensation, two molecules of ammonia are eliminated. The reaction is very sensitive to the presence of ZnO. Without this catalyst, a yield of 20% is reported together with the formation of several by-products. The reaction was also carried out under reduced pressure... 

The benzyl phosphonate triesters 100 reacted with isocyanates under similar conditions to give the corresponding cyclic urea phosphonate diesters 101 (2). 

Lam PYS, Jadhav PK, Eyermann CJ, Hodge CN, Ru Y, Bacheler LT, Meek JL, Otto MJ, Rayner MM, Wong YN, Chang CH, Weber PC, Jackson DA, Sharpe TR, Erickson-Viitanen S. Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors. Science 1994 263 380-4. 

Incorporation of the position of water molecules that are firmly bound to the protein can impart affinity and novelty to the designed ligand. A prime example is the design of a class of HIV protease cyclic urea inhibitors by DuPont scientists that incorporated a water molecule bound to both flaps of the enzyme into their ligand [32]. The crystal structure of the HIV protease-cyclic urea complex [32] shows the urea carbonyl oxygen substituting for the position of the water molecule. 

Diazidobiphenyl is transformed by diiron nonacarbonyl into a cyclic urea together with a small amount of the bridged dinuclear complex 142 the latter is a minor product but it can be converted oxidatively into benzocinnoline (Scheme 165).191... 

Kim and Varma have described the preparation of a range of cyclic ureas from diamines and urea [366]. In the example highlighted in Scheme 6.203, ethylenedi-amine and urea were condensed in the presence of 7.3 mol% of zinc(II) oxide in N,N-dimethylformamide as solvent at 120 °C to furnish imidazolidin-2-one in 95% isolated yield. Key to the success of this method is that the reaction needs to be performed under reduced pressure in order to remove the ammonia formed from the reaction mixture. This method was extended to a variety of diamines and amino alcohols [366]. 

Cyclic ureas incorporating a 1,3-diazepinone skeleton continue to be of pharmacological interest. The Ai V-disubstituted system 89 has been prepared and shown to be a potent inhibitor of factor Xa in vitro and to have an improved pharmacokinetic profile in the rabbit. The binding model for this series of compounds was confirmed by an X-ray crystallographic analysis of one analogue in the series <00BMCL301>. 

The guanidino analogue 90 of the 7-membered cyclic urea system was prepared, enantiomerically pure, from D-mannitol. The derivative 90 selectively inhibits bovine kidney a-L-fucosidase at 2.8pM <00BMC307>. 

Warshel and coworkers have recently examined the LIE method and different versions of what they call the LRA (linear response approximation) method for the binding of a set of cyclic urea compounds to HIV protease.34 The key features of their LRA scheme is that both averages of Equation 2 are evaluated, thus requiring two extra simulations of the non-polar states (see above), that the ligand intramolecular electrostatic terms are included in the averages, and that the non-polar contribution is calculated with the PDLD method. Results of similar quality were reported with the different methods.34 However, it should be noted that the value Vi of the electrostatic coefficient was used in Ref. 34, which, as discussed above, has been shown... 

N-( 1,1 -Dialkylprop-2-ynyl)ureas, bearing a bidentate ureic function, afforded oxazoline and cyclic ureas derivatives simultaneously, depending on whether the cyclization was initiated by the oxygen or the nitrogen atom (Eq. 46) [106]. The nature of the nitrogen substituent strongly influenced the product distribution. 

Intramolecular trapping was also possible, as exemplified by the synthesis of cyclic ureas (Eq. 53) [275] and oxazolidin-2-ones [232,234] (Eqs. 54 and 55). 

Symmetrical dialkyl and diaryl thioureas have been prepared in generally good yield (60-90%) from the reaction of the amine with thiophosgene, formed in situ from the catalysed reaction of carbon tetrachloride with sodium sulphide [5], Reaction with diamines yields cyclic ureas. 

Eaton and co-workers ° synthesized the cubane-based dinitrourea (42) via iV-nitration of the cyclic urea (41) with nitric acid-acetic anhydride. Cubane-based nitramide (43) is prepared from the IV-nitration of the corresponding bis-amide with acetic anhydride-nitric acid. Bis-nitramine (44) is prepared from the IV-nitration of the corresponding diamine with TFAA-nitric acid. ... 

It is of interest to note that a simple tetrahydropyrimidine, such as the 2-hydroxy derivative (XCIX), which actually is a cyclic urea, with the two protons probably on the nitrogen atoms, rather than the tautomer shown here. 

Many other non-peptide inhibitors of HIV protease (dihydropyrone, cyclic urea and sulphamide series of compounds) were obtained by modifications of random screening leads. Examples of these include a cyclic sulph-one derivative 147 and 148 (PNU-140690) that showed activity against a variety of HIV t)rpe 1... 

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