Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1995-11-02
1998-08-18
Fonda, Kathleen K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 54, 536 41, 536 53, 536 54, 536 55, 536 553, 536124, A61K 3170, C07H 1500
Patent
active
057958696
DESCRIPTION:
BRIEF SUMMARY
This is the U.S. National stage entry under 35 U.S.C. 371 of PCT/US94/01966, filed Mar. 4, 1994.
OBJECT OF THE INVENTION
The present invention concerns novel semisynthetic ganglioside analogues, and more precisely N-sulfo-, N-hydrocarbylsulfonyl- and N-hydrocarbyloxysulfonyl-N,N'-dilyso-gangliosides and the N'-acyl derivatives thereof, N'-sulfo-, N'-hydrocarbylsulfonyl- and N'-hydrocarbyloxysulfonyl-N,N'-dilyso-gangliosides and the N-acyl derivatives thereof, N,N'-di or polysulfo-N,N'-di- or poly-lyso-gangliosides, N,N'-di or polyhydrocarbylsulfonyl-N,N'-di or poly-lyso-gangliosides and N,N'-di- or polyhydrocarbyloxysulfonyl-N,N'-di or polylyso-gangliosides and the functional derivatives thereof, and salts of all these compounds.
The novel derivatives have interesting pharmacological properties, especially protective activity against neurotoxicity induced by excitatory amino acids, such as glutamic acid, and can therefore be used in therapy for the nervous system, such as for conditions following degeneration or lesions, i.e., ischemia, hypoxia, epilepsy, trauma and compression, metabolic dysfunction, aging, toxic-infective diseases and chronic neurodegeneration, such as Alzheimer's disease, Parkinson's disease or Huntington's chorea.
The novel compounds of the invention, thanks to their neuritogenic activity, can be used to advantage in therapies aimed at nervous function recovery, such as in peripheral neuropathies and pathologies associated with neuronal damage.
Moreover, the novel derivatives which are object of the present invention have valuable properties for the modulation of the expression of specific determinants, such as CD.sub.4, present on the surface of human cells belonging to the immune system.
The ability of the above compounds to modulate expression of the molecule CD.sub.4, a membrane glycoprotein expressed in various cell types such as thymocytes, lymphocytes, monocytes and macrophages has great applicative potential in a wide range of human pathologies.
Compounds of the present invention may have therapeutic use in all situations wherein it is necessary to prevent and/or treat infections involving CD.sub.4+ cells, such as infections the etiological agents whereof are microorganisms belonging to the human immunodeficiency (HIV) family of viruses. Moreover, the modulation of CD.sub.4 is useful in systemic or organ-specific autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, chronic polyarthritis, lupus erythematosus, diabetes mellitus, and also to prevent the phenomenon of organ transplant rejection as well as rejection by the transplanted material against the host, as in the case of bone marrow transplant, and in all cases where the desired effect is to obtain tolerance towards "self" and "non-self" antigens.
Functional derivatives of the abovesaid semisynthetic ganglioside analogues are for example esters and amides of the carboxyl groups of sialic acid residues and may also be inner esters with lactone bonds between their sialic carboxyl groups and hydroxyl groups in the oligosaccharide, analogous to those known in the case of gangliosides, and possibly also the derivatives of all these compounds, in which the hydroxyl groups are esterified with organic acids or sulfuric acid.
Of particular interest are the esters with organic acids wherein all the hydroxyl groups, both those of the saccharide component and the free groups of sialic acid, and the hydroxyl group of the ceramide residue are esterified, that is "peracylated" and also the persulfated derivatives, i.e. those wherein all the hydroxyl groups are esterified with sulfuric acid.
The term "N,N'-dilyso-ganglioside" in the aforesaid definition means a ganglioside from which both the acyl group on the amino group in its ceramide residue, and the acyl group(s) of its sialic acid residue(s) have been removed. In the new compounds of the invention the ceramide amino group (position N) or all the amino groups of sialic acid (a position which is collectively called N' for brevity), or both the free amino functions
REFERENCES:
patent: 5350841 (1994-09-01), Romeo et al.
Olney Annu. Rev. Pharmacol. Toxicol. 1990, 30, 47-71.
Greene Scientific American 1993, 269(3), 99-105.
Fauci Proc. Natl. Acad. Sci. USA Dec. 1986, 83(24), 9278-9283.
Handa et al. Biochem. Biophys. Res. Commun. Feb. 28, 1991, 175(1), 1-9.
Chizzolini Carlo
Facci Laura
Kirschner Gunter
Manev Hari
Romeo Aurelio
FIDIA S.p.A.
Fonda Kathleen K.
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