Carbohydrates and use thereof

Details Carbohydrates and use thereof Carbohydrates and use thereof

1999-12-06

2002-07-23

Gitomer, Ralph (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C514S054000

Reexamination Certificate

active

06423832

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to carbohydrate derivatives having an immunomodulating effect, pharmaceutical compositions containing the same, and use of the carbohydrate derivatives in the manufacture of a medicament for therapy.
BACKGROUND ART
Immunomodulators, in the following referred to as IMs, are a group of non-endogenous compounds which modulate macrophages and related cell types, thereby stimulating or down-regulating the immune defence of the body. In most cases this modulation consists of a stimulation of macrophages and related cell types.
By the term “macrophages” is meant, inter alia, cells having the capability of enclosing particles having a size of about 1-10 &mgr;m and additionally affecting their environment by means of secretion of biologically active substances. The term “macrophages” also comprises related cell types, such as coelomocytes and most phagocytes of lower animals (invertebrates), promonocytes, monocytes, Kupffer cells, microglial cells, histiocytes and tissue macrophages of higher animals (vertebrates) and various types of syncytia cells and giant cells which are formed by fusion with individual macrophages.
A large number of IMs consist of carbohydrates, such as &bgr;1→3-glucans and alginates (salts of polymannuronic acid), or contain carbohydrate units, such as bacterial lipopolysaccharides, LPS and peptidoglycans. Some of these compounds, for instance LPS, are toxic and consequently not suitable for use in human or veterinary medicine in those cases where an immunity-enhancing effect is desired. Other IMs, such as &bgr;1→3-glucans, seem to be virtually nontoxic although they have a clear biological activity both in vitro and in vivo. As examples of pharmacological effects caused by the latter compounds mention can be made of, inter alia, strong stimulation of the production of cytokine, nitric oxide and arachidonic acid metabolites in macrophages (Seljelid, R. and Eskeland, T.,
Eur J. Haematol
., 51, 267-275, 1993; Seljelid, R. and Busund, L.-T. R.,
Eur J. Haematol
., 52, 1-12, 1994; Sveinbjørnsson, B., Olsen, R., Seternes, O. M. and Seljelid, R.,
Biochem. Biophys. Res. Comm
., 223, 643-649, 1996), resistance to lethal infections in both mammals and lower vertebrates (animals) and invertebrates (Dalmo, R. A., Bøgwald, J., Ingebrigtsen, K. and Seljelid, R.,
J Fish Diseases
, 19, 449-457, 1996; Busund, L-T., Rasmussen and Seljelid, R., in
Molecular Pathogenesis of Surgical Infections
, Wadström. T., Holder, I. A., Kronvall, G. (eds.),
Proceedings of the Eric K. Fernström Symposium
, Lund, pp 293-302, 1992), regression of syngeneic tumours in mice (Seljelid, R.,
Bioscience Reports
, 6, 845-851, 1986; Seljelid, R.,
Scand. J. Immunol
., 29, 181-192, 1989) and prevention of metastases in experimental tumours in rats (Sveinbjørnsson et al, in press).
In those cases where carbohydrate immunomodulators, below referred to as CIMs, have been hydrolysed in connection with the production of oligosaccharides, the biological activity in general has disappeared (Seljelid, R., Bøgwald, J. and Lundwall, Å.,
Exp. Cell. Res
., 131, 121-129, 1981; Seljelid, R. et al,
Scand. J. Immunol
., in press, 1997).
It is also known to modify existing CIMs while maintaining their biological activity in respect of stimulation of macrophages in vitro. Such a modification is the substitution of a hydroxyl group with an amino group (Bøgwald, J., Seljelid, R. and Hoffman. J.,
J. Carbohydr. Res
., 148, 101-107, 1986; Rasmussen, L.-T. and Seljelid, R.,
Scand. J. Immunol
., 32, 321-331, 1990), the resulting aminated &bgr;1→3-glucan besides being found to be water-soluble contrary to the non-modified &bgr;1→3-glucan. This may be caused by the fact that precisely the hydroxyl groups which are important to the aggregate formation in &bgr;1→3-glucan (vide infra), which aggregate formation lowers its solubility, have been substituted by amino groups which complicate the aggregate formation, resulting in the net effect that the solubility increases significantly in said amino substitution.
U.S. Pat. No. 4,795,745 A discloses a composition in which soluble &bgr;1→3-glucan has been bound to a water-insoluble carrier, which results in a composition which accomplishes activation of macrophages.
Another type of modified &bgr;1→3-glucan is disclosed in JP 04-2140701 A, in which the hydroxyl groups of a &bgr;1→3-glucan having a molecular weight from 200 and 800 g/mole have been etherified with both lower hydroxyalkyl groups having 2-4 carbon atoms and higher alkyl groups having 8-26 carbon atoms. These compounds are used for e.g. cosmetic and medicinal purposes.
General Description of the Invention
A common denominator of the carbohydrates, and especially &bgr;1→3-glucans, which are known up to now as immunomodulating substances is that their binding to receptors on the cell surfaces of macrophages and related cell types mainly occurs via hydrogen bonds. This is obvious when observing that the most important functional groups in addition to the actual carbon skeleton are either hydroxyl or amino groups, below referred to as hydrogen-binding groups, which both have the capacity of binding to, for instance, a receptor by means of hydrogen bonds. If one or more of these hydrogen-binding groups are replaced with non-hydrogen-binding groups, the binding of the compounds to the receptor or receptors will therefore probably be weakened since the substrate, i.e. the carbohydrate, loses one or more binding positions. The weakening will probably be greater, the lower hydrogen-binding capacity the substituting group presents. Moreover, steric hindrances, if any, are often important to the binding, and since both hydroxyl and amino groups from a sterical point of view are relatively unhindered groups, a sterically hindered substituent for one of these groups may weaken the binding to the receptor or receptors. As a rule, the weakening of the binding increases, the more sterically hindered the substituent is.
Summing up the above discussion, it may therefore be established that a substituent to hydroxyl or amino groups which has both a lower hydrogen-binding capacity and a larger sterical hindrance than any one of the above-mentioned groups is in the first place expected to cause a weakening of the binding of a carbohydrate to a receptor.
However, according to the present invention it has surprisingly been found that immunomodulating carbohydrates which have been etherified with aliphatic hydrocarbon chains have an immunomodulating effect and, thus, stimulate machrophages and related cell types. For these etherified immunomodulating carbohydrates, the expected weakening of the receptor binding to the macrophages has thus not occurred.
The IMs which consist of pure carbohydrates, such as &bgr;1→3-glucans, alginates and agarose, are of course hydrophilic, but are all the same poorly soluble in water owing to their high molecular weight in combination with aggregate formation and intermolecular hydrogen bonds. Since these properties often reduce the general bioavailability of the compounds, this is disadvantageous for their use as pharmaceutical preparations, above all in respect of, inter alia, dosage, uptake, distribution and biological half-life in the body after administration. It is known (vide supra) that modified &bgr;1→3-glucans are often more easily water-soluble than the non-modified starting material in spite of a seemingly insignificant modification of the said type of compound. It thus seems probable that also minor changes are in many cases sufficient to considerably affect, for instance, intermolecular hydrogen bonds and aggregate formation, which to a high extent cause the insignificant water solubility of many non-modified IMs.
The etherification of the compounds according to the present invention supplies an improvement of the lipophilic properties of the compounds. These new lipophilic properties affect, inter alia, dosage, uptake, distribution and biological half-life in the body after administr

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