Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1996-01-31
1998-12-15
Fonda, Kathleen K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
536 172, 536 175, 536 176, 536 179, A61K 3170, C07H 1500
Patent
active
058497170
DESCRIPTION:
BRIEF SUMMARY
This application is based on PCT International Application Number PCT/US94/01965 filed Mar. 4, 1994.
OBJECT OF THE INVENTION
The present invention relates to novel derivatives of gangliosides and of N-acyl-N-lyso-gangliosides, of N'-acyl-N'-lyso-gangliosides and N,N'-di- or poly-acyl-N,N'-dilyso-gangliosides, whereof at least one of the hydroxyl groups of the saccharide, sialic or ceramide residues is esterified with sulfuric acid, the functional derivatives thereof, and their salts with either inorganic or organic bases and the acid addition salts, except persulfated derivatives at their hydroxyl groups in the saccharide, sialic and ceramide moieties of the gangliosides GM.sub.1, GD.sub.1a, GD.sub.1b, and GT.sub.1b.
Furthermore, the present invention concerns pharmaceutical preparations comprising the novel derivatives of gangliosides mentioned above and their therapeutical application.
The novel derivatives have interesting pharmacological properties, especially protective activity against neurotoxicity induced by excitatory amino acids, such as glutamic acid, and are therefore foreseen to 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, may be used advantageously in therapies aimed at nervous function recovery, such as in peripheral neuropathies and pathologies associated with neuronal damage.
Moreover, certain 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 CD.sub.4 molecule, 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.
The novel derivatives of the present are contemplated to be used therapeutically in all situations wherein it is necessary to prevent and/or treat infections involving CD.sub.4+ cells, such as in infections, the etiological agents whereof are microorganisms belonging to the human immunodeficiency (HIV) family of viruses.
Moreover, modulation of CD.sub.4 is useful in systemic or organ-specific autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, chronic polyarthritis, lupus erythematosus, juvenile-onset 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.
The term "N,N'-di-lyso-gangliosides" in the aforesaid definition means a ganglioside from which the natural acyl groups have been removed from the neuraminic nitrogen (N') and from the sphingosine nitrogen (N) thus leaving free amino groups; the word "-di" stands thus to indicate the two positions N and N', but not the actual number of the free amino groups which, depending on the number of sialic acids present, can be more than 2. The expression "N-acyl-N'-di-" or "poly-acyl" is used in the case of synthetic analogues of gangliosides substituted in both the positions N and N'.
The functional derivatives of the abovesaid semisynthetic ganglioside analogues are for example the esters and amides of the carboxyl groups of sialic acid residues, and may also be inner esters with lactone bonds between the sialic carboxyl groups and the hydroxyls of the oligosaccharide, analogous to those known in the case of gangliosides, and possibly also the derivatives of all these compounds, the hydroxyl groups thereof being esterified with organic acids.
Of particula
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Tiemeyer, et al., "Ganglioside-specific . . .", The Journal of Biological Chemistry, vol. 264, No. 3, Jan. 25, 1989, pp. 1671-1681.
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Chizzolini Carlo
Facci Laura
Kirschner Gunter
Manev Hari
Romeo Aurelio
FIDIA S.p.A.
Fonda Kathleen K.
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