6632-11-7

The invention relates to derivatives of 2-hydroxytetrahydrofuran corresponding to general formula (I) in which A represents the radical, in which R1, R2, R4, R5 and R6 represent (in particular), independently, H, a halogen atom, OH, alkyl or alkoxy, R3 represents H, alkyl or —COR10, R10 representing H, alkyl or alkoxy, and W represents a bond, —CH2—CH2—, —CH═CH—, —O—, —S— or —NR11— in which R11 represents H or alkyl; X represents —CO—, —Y—CO—, —O—Y—CO— or —NR12—Y—CO—, Y represents an alkylene or haloalkylene alkyl, R12 represents H, alkyl or —COR13, R13 represents H, alkyl, haloalkyl or alkoxy, AA represents, each time that it occurs, a natural or non-natural amino acid; n represents 2 or 3; and finally R represents H, alkyl or —CO—R19, R19 representing alkyl. These compounds have a calpain inhibiting activity and/or an activity which traps the reactive oxygen species and can be used for preparing a medicament intended to treat the inflammatory and immunological diseases, cardio-vascular and cerebro-vascular diseases, disorders of the central or peripheral nervous system, cachexia, osteoporosis, muscular dystrophy, proliferative diseases, cataract, rejection reactions following organ transplants and autoimmune and viral diseases.

Given the role of trypanothione in the redox defenses of pathogenic trypanosomal and leishmanial parasites, in contrast to glutathione for their mammalian hosts, selective inhibitors of trypanothione reductase are potential drug leads against trypanosomiasis and leishmaniasis. In the present study, the rational drug design approach was used to discover tricyclic neuroleptic molecular frameworks as lead structures for the development of inhibitors, selective for trypanothione reductase over host glutathione reductase. From a homology-modeled structure for trypanothione reductase, replaced in the later stages of the study by the X-ray coordinates for the enzyme from Crithidia fasciculata, a series of inhibitors based on phenothiazine was designed. These were shown to be reversible inhibitors of trypanothione reductase from Trypanosoma cruzi, linearly competitive with trypanothione as substrate and noncompetitive with NADPH, consistent with ping-pong bi bi kinetics. Analogues, synthesized to define structure-activity relationships for the active site, included N-acylpromazines, 2-substituted phenothiazines, and trisubstituted promazines. Analysis of K(i) and I50 data, on the basis of calculated log P and molar refractivity values, provided evidence of a specially favored fit of small 2-substituents (especially 2-chloro and 2-trifluoromethyl), with a remote hydrophobic patch on the enzyme accessible for larger, hydrophobic 2-substituents. There was also evidence of an additional hydrophobic enzymic region available to suitable N-substituents of the promazine nucleus. K(i) data also indicated that the phenothiazine nucleus can adopt more than one inhibitory orientation in its binding site. Selected compounds were tested for in vitro activity against Trypanosoma brucei, T. cruzi, and Leishmania donovani, with selective activities in the micromolar range being determined for a number of them.

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