Lysoganglioside derivatives

Details Lysoganglioside derivatives Lysoganglioside derivatives

1994-06-30

2002-06-18

Fonda, Kathleen K. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S054000, C536S004100, C536S053000, C536S055100, C536S122000

Reexamination Certificate

active

06407072

ABSTRACT:

The present invention is directed to new lysoganglioside derivatives and more particularly to novel N-acyl lysogangliosides, in which the acyl group is derived from an aliphatic acid substituted by one or more polar groups.
Lysogangliosides are derivatives obtainable from gangliosides by deacylation of the ceramide group, which retain only the sphingosine residue. Gangliosides are generally mixtures of various unitary chemical compounds having the following formula:
These molecules contain an oligosaccharide part, generally well defined chemically for each ganglioside, a sialic part (that is, constituted by one or more sialic acids) and a ceramide part, these last three parts being generally constituted by a mixture of different sialic acids and different ceramide residues.
Sialic acids are acyl derivatives of neuraminic acid of the formula
wherein the amino group is acylated with acetic or glycolic acid and the hydroxyl groups may also be esterified with such acids. The ceramide group represents an N-acylsphingosine corresponding to one of the two following formulae:
in which n is 6 to 18 and the acyl group is derived from a saturated or unsaturated fatty acid having from 16 to 22 carbon atoms or from a corresponding hydroxy acid. As noted above, in gangliosides the sialic and ceramide residues are mixtures of the groups having the above formulae, and this is true also for the purified gangliosides described in the literature. The number of sialic acids present in gangliosides usually varies between 1 and 5. The sialic residues are bound to the oligosaccharide by a ketosidic bond formed by the hydroxyl at the 2-position with a hydroxyl group in the oligosaccharide. When several sialic acids are bound together, the union between them is brought about by ketosidic bonds formed between the hydroxyl groups at the 2- and 8-positions of two sialic acid molecules. The sialic acids of gangliosides, and of those which are purified as previously described, are mixtures of various chemically unitary acids, for example, N-acetylneuraminic acid and N-glycolylneuraminic acid, in which the former is predominant, and possibly of one or more of their O-acylderivatives, for example, the 8-O-acylderivatives.
The oligosaccharide is composed of a maximum of 5 monosaccharides or derivatives thereof with an acylamino group, especially hexoses and their derivatives of the above-mentioned type. There is, however, always present in the oligosaccharide at least one glucose or galactose molecule, the most frequent residue as the acylamino derivative of the above-mentioned sugars being N-acetylglucosamine and N-acetylgalactosamine. Lysogangliosides, as defined above, can be obtained by enzymatic deacylation of the nitrogen on the ceramide. If deacylation is effected chemically, for example, by alkaline hydrolysis, other esterified acylamino or hydroxy groups are deacylated, such as, especially, the acyl present on the nitrogen of the neuraminic or acyl acids possibly present, (usually to a lesser degree) on the hydroxy groups of such acids.
As has been noted above, the acyl groups present in gangliosides on the nitrogen of the neuraminic acid are derived from acetic acid and possibly, to a far lesser degree, from glycolic acid. Selective reacylation, for example, after temporarily protecting the sphingosine amino group, gives products of the type of lysogangliosides obtained by enzymatic deacylation, which differ therefrom only in the exclusive presence of the acetyl group on the neuraminic nitrogen and possibly in the absence of acylating groups on the hydroxyl groups of this acid. This group of deacylated derivatives also serves as a substrate for the preparation of new N-acyl lysogangliosides, and the term “lysogangliosides” is used in the present application to mean both the products of enzymatic deacylation and products obtained in the above-said manner by chemical deacylation.
The compounds of the present invention are semisynthetic analogues of gangliosides and differ therefrom due to the presence of a single well-defined N-acyl group in the sphingosine part and with acids which are very different from those of natural products. They are new, even though among natural gangliosides, products have been found which, when hydrolyzed, give rise to the formation of higher aliphatic acids substituted by hydroxy groups (and therefore polar groups, such as those of the present invention). However, the corresponding products have never been isolated and have never been described. The invention also includes functional derivatives of the sialic carboxy groups of the new N-acyl lysogangliosides, that is, esters and amides, and also inner esters having lactone bonds among the sialic carboxy groups and hydroxyl groups of the oligosaccharide, analogues and known derivatives of gangliosides, as well as peracylated derivatives of the hydroxyl groups of the ganglioside, both of N-acyl lysogangliosides themselves and of their functional derivatives as mentioned above.
The main object of the present invention is directed to N-acyl lysogangliosides, in which the acyl group is derived from an aliphatic acid having from 2 to 24 carbon atoms, substituted by one or more polar groups chosen from the following group:
chlorine, bromine and fluorine;
free hydroxy groups or hydroxy groups esterified with an organic or inorganic acid;
etherified hydroxy groups;
keto, ketal and acetal groups derived from lower aliphatic or araliphatic alcohols;
ketoxime, aldoxime or hydrazone groups optionally substituted by lower alkyl or aralkyl groups;
free mercapto groups or mereapto groups esterified with a lower aliphatic or araliphatic acid or etherified with lower aliphatic or araliphatic alcohols;
free or esterified carboxy groups;
free sulfonic acid groups or sulfonic groups esterified with lower aliphatic or araliphatic alcohols;
sulfamide or sulfamidic groups substituted by lower alkyl or aralkyl groups or lower alkylene groups;
sulfoxide or sulfone groups derived from lower alkyl or aralkyl groups;
nitrile groups;
free or substituted amino groups, and quaternary ammonium derivatives of such amino groups; or
esters and/or amides of the sialic carboxy groups of said N-acyl-lysogangliosides, inner esters of said N-acyl-lysogangliosides, metal salts or organic base salts of said N-acyl-lysogangliosides having acid groups, acid addition salts of said N-acyl-lysogangliosides and the corresponding derivatives of mixtures of said N-acyl-lysogangliosides.
The invention is also directed to pharmaceutical preparations containing one or more of the above-mentioned derivatives of lysogangliosides or their mixtures, or the respective salts, as well as their therapeutic use and methods for their preparation.


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