Esters of D-mannose or of xylitol and their use as medicaments

Details Esters of D-mannose or of xylitol and their use as medicaments Esters of D-mannose or of xylitol and their use as medicaments

1997-03-11

1998-11-03

Kight, John

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

514 25, 536 41, 536115, 536119, 536120, 536116, 568852, A61K 3170, C07H 1302, C07H 1504, C07H 100

Patent

active

058308725

DESCRIPTION:

BRIEF SUMMARY
The application is a 371 of PCT/FR95/00743, which was filed Jun. 7, 1995.
The present invention relates to esters combining phenylacetic, 3-phenylpropionic, 4-phenylbutyric and n-butyric acids with D-mannose, with xylitol and with their derivatives, and to their applications as medicaments.
It is known that phenylacetic, 4-phenylbutyric and n-butyric acids and their salts stimulate the synthesis of foetal haemoglobin, in particular that of the .gamma. chain (E. Fibach et al., Blood (1993),82 (7), 2203; S. P. Perrine et al., Biochem. Biophys. Res. Comm. (1987), 148, 694). Moreover, they induce the .gamma. gene of human foetal haemoglobin (J. W. Zhang et al., Developmental Genetics (1990), 11, 168; J. G. Glauber et al., Molec. Cell Biol. (1991), 11, 4690). These properties have been turned to good account in the treatment of patients affected by anaemia and by .beta.-thalassaemic syndromes (S. P. Perrine et al., N. Engl. J. Med. (1993), 328, (2), 81).
It is also known that these acids and their salts inhibit the growth and induce the differentiation of premalignant and malignant cells (D. Samid et al., Cancer Res. (1992), 52, 1988; E. Ginsburg et al., Proc. Natl. Acad. Sci. (1973), 70, 2457; K. Yamada et al., J. Cell. Physiol. (1985), 125, 235; K. N. Prasad, Life Sciences (1980), 27, 1351), in particular of leukaemic cells (S. Fisckhoff et al., Leukemia (1990), 4, 302; D. Samid et al., Cancer Res. (1992), 52, 1988).
It is also known that n-butyric acid and its salts have a very short in vivo plasma lifetime (P. Daniel et al., Clin. Chim. Acta (1989), 81, 255). It is also known that esters resulting from the combination, via a covalent bond, of this acid with D-glucose, with D-galactose, with glycerol and with their derivatives are capable, in vivo, under the effect of the enzymatic systems in man or in animals, of slowly releasing n-butyric acid with, as a result, a much longer plasma lifetime, thus providing a better bioavailability of the biologically active part (F. Pieri et al., Patent FR 871294 (1987); Patent FR 8809092 (1988); PCT 88004470 (1988); U.S. Pat. No. 071501 (1990)).
It is also known, from biological studies of the butyric esters mentioned above, that the best compound as a medicament is the monoester 3-O-n-butanoyl-1,2-O-isopropylidene-.alpha.-D-glucofuranose (P. Pouillard, Thesus, Amiens, 1990; P. Planchon, Thesus, Amiens, 1991). However, this compound, as a result of its structure exhibiting 2 hydroxyl groups OH in the region of the O-n-butanoyl group, undergoes an internal transesterification resulting, in solution, in the mixture of the 3 3-O-butanoyl, 5-O-butanoyl and 6-O-butanoyl isomers in proportions which vary according to the operating conditions. Moreover, the isomerization of this compound continues in a non-controllable way when the sample is dissolved, in particular in aqueous medium. This isomerization is in accordance with the laws of chemistry, when, in a compound, a primary hydroxyl group is sterically close to an ester group bonded to a secondary site and when this hydroxyl group has a steric orientation favourable to the attack of the neighbouring acyl group (P. Y. Goueth et al., J. Carbohydr. Chem. (1994), 13 (2), 249). It is consequently impossible to obtain this compound with a purity greater than 95%.
One of the aims of the present invention is to prepare esters combining phenylacetic, 3-phenylpropionic, 4-phenylbutyric and n-butyric acids with monosaccharides or itols (sugar-alcohols) Su(OH).sub.n selected so that their structure or that of their derivatives prevents the internal transesterification process responsible for the isomerization, while making possible good bioavailability of the corresponding acid.
The aim is achieved according to the invention by the synthesis, for example, of esters of general formula: ##STR1## in which the monosaccharide or itol (sugar-alcohols) Su(OH).sub.n, the precursor of the compounds in accordance with the invention, is preferably xylitol carrying the ester group on the C-1 primary carbon atom; 4-phenylbutanoyl or n-butanoyl grou

REFERENCES:
patent: 3053677 (1962-09-01), Touey
patent: 3862121 (1975-01-01), Jaques et al.
patent: 5185436 (1993-02-01), Villa et al.
Industrial Inorganic Chemicals, vol. 76, 1971 (1 pg) No. 20 Nov. 15, 1971 Columbus Ohio.

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