A retroviral protease inhibiting compound of the formula A--X--B is disclosed. Also disclosed are a composition and method for inhibiting a retroviral protease and for treating an HIV infection. Also disclosed are processes and intermediates useful for the preparation of the retroviral protease inhibitors.

Retroviral protease inhibiting compounds.

Further advances in the chemistry of mannich bases

Publisher Summary This chapter provides information on the chemistry and pharmacology and physicochemical properties of barbiturates, along with the tautomerism and solvation of the barbituric acid ring. Barbituric acid exists in the solid state in the trioxo structure. NMR investigation of the oxo-hydroxy equilibrium indicates that only the oxo form is present in a solution in anhydrous DMSO. Several spectral properties of the barbituric acid are discussed using UV spectra, infrared and Raman spectroscopy, 1 H-NMR spectroscopy, 13 C-NMR spectroscopy, and mass spectrometry. In the crystalline state, barbiturates show several modes of intermolecular hydrogen bonding, which differ by the number of hydrogen bonds formed between the NH and CO groups. These hydrogen bonds are responsible for layer packing in the crystal lattice. Weak intermolecular van der Waals interactions of carbonyl groups are also responsible for the three-dimensional packing of the molecules in the crystal structure.

Recent Progress in Barbituric Acid Chemistry

Clay catalyzed chemoselective Michael type addition of aliphatic amines to α,β-ethylenic compounds

Allylamines function as substrates for cross-coupling with boronic acids in the presence of nickel(0) catalysts rather than palladium(0) catalysts. Aryl,- vinyl- and methyl-boronic acids function well. With vinyl derivatives, E-isomers couple more efficiently than Z-isomers and both fully retain the geometrical integrity. Methylations preferably employ the boronic esters like 2-methyl-1,3,2-benzodioxaborole or 2-methyl-1,3,2-dioxaborolane rather than methylboronic acid. The stereochemistry of the reaction involves a net inversion with respect to the allylamine. The regioselectivity is a function of ligand. Generally, sterically bulky donor phosphines promote new C–C bond formation at the less substituted position. Bidentate ligands, notably 1,1′-binaphthyl-2,2′-ylbis(diphenylphosphinite)(BINAPO), promote new C–C bond formation at the more substituted allyl terminus. The amines appear to be the preferred partner compared to allyl alcohols and esters with the boronic acids and give higher stereospecificity.

Keynote article. Nickel catalysed coupling of allylamines and boronic acids

New types of methylene compounds, N-alkylthiomethyl derivatives of N-alkyl (or aryl) hydroxylamines and N, N-bis (alkylthiomethyl) hydroxylamines, have been obtained by Mannich-type condensation using thiols, formaldehyde and hydroxylamines.

Preparation of N-Alkylthiomethyl Derivatives of Hydroxylamines

The Leuckart-Wallach reaction paths were investigated by means of catalytic reduction in the Leuckart-Wallach reaction system and on the basis of analogous formic acid reductions. It was determined that, in the early stage of the Leuckart-Wallach reaction, ammonia, amine and also formamide undergo addition reactions to carbonyl compounds. The addition of formamide catalyzed by formic acid plays a significant role only for the more reactive substrates such as benzaldehyde. The behaviors of plausible intermediates for the formic acid reduction are discussed on the basis of the data of similar formic acid reductions.

Studies on Leuckart-Wallach Reaction Paths

The substitution of the dialkylamine residue of N-(dialkylaminomethyl) amides with nucleophiles leading to the formation of the amidomethyl compounds, reported in several papers by Hellmann, et al. has been shown not to occur with sulfides and cyanide under the condition of heating in methanol preferably in the presence of sodium hydroxide, whereas the substitution of the amide residue is chiefly effected. By similar manners the substitution reactions of N-(α-dialkylaminobenzyl) amides with sulfides and cyanide have been also realized.

Reaction of N-(Dialkylaminomethyl) amides and N-(α-Dialkylaminobenzyl) amides with Sulfides and Cyanide

Conformational analysis by means of nuclear magnetic resonance measurement has disclosed that N-[(N-nitrosoalkylamino) methyl] amides newly prepared are in favor of anti form in crystals while in state of solution form syn-anti equilibrium mixture. These nitrosoamines have been found smoothly to generate diazoalkanes by the influence of alkali. In the use of their benzamide analogs a new practically useful means for synthesizing a series of diazoalkanes has been established.

A New Convenient Synthesis of Diazoalkanes from N-[(N-Nitrosoalkylamino) methyl] benzamides

Catalytic hydrogenolyses of the benzylidene compounds, in which two oxygens, two nitrogens and both oxygen and nitrogen are bound to the α-carbon of the benzylidene, were investigated in order to know the condition of hydrogenolysis, which may affect one of the two bonds, if possible, and either one of the two when the two are different. Partial hydrogenolyses of the N, N'-benzylidenediamines and O, O'-benzylidenediethers and selective hydrogenolyses of the α-alkoxybenzylamines and N-(α-aminobenzyl) amides were realized by the method of using palladium-on-charcoal and Raney nickel catalyst. The catalytic hydrogenolyses of the latter two were influenced by solvent used and were selectively effected at the carbon-oxygen bond of the α-alkoxybenzylamines and at the carbon-amine nitrogen or carbon-amide nitrogen bond of the N-(α-aminobenzyl) amides.

Keiichi Ito

Papers

Preparation of N-Alkylthiomethyl Derivatives of Hydroxylamines

Studies on Leuckart-Wallach Reaction Paths

Reaction of N-(Dialkylaminomethyl) amides and N-(α-Dialkylaminobenzyl) amides with Sulfides and Cyanide

A New Convenient Synthesis of Diazoalkanes from N-[(N-Nitrosoalkylamino) methyl] benzamides

Catalytic Hydrogenolyses of Benzylidene Compounds Bound to Two Oxygens, Two Nitrogens and Both Oxygen and Nitrogen