Guanylic acid derivatives and their use as drugs

Details Guanylic acid derivatives and their use as drugs Guanylic acid derivatives and their use as drugs

1997-01-29

1998-04-07

Henley, III, Raymond

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

536 2781, A61K 3170, C07H 19167

Patent

active

057365300

DESCRIPTION:

BRIEF SUMMARY
This is a 371 of PCT/FR95/00806 filed Jun. 16, 1995.
The present invention relates to guanylic acid derivatives and the use of these substances as drugs.
The molecule of 5'-guanylic acid and the processes for obtaining this molecule have already been described in the literature. In particular reference is made to this product in the Merck Index, 11.sup.th edition (Reference N.degree. 4484). It is known that this molecule in the form of a sodium salt may be used as a flavouring.
Also, this molecule has an important physiological role. Guanylic acid is a precursor of cyclic GMP which plays a known part in micro-circulation.
A physiological balance exists both between adenosine and guanosine and between the two cations calcium and magnesium. The excess of intracellular calcium and adenosine observed in elderly people leads to slowing of intellectual activity and asthenia. Magnesium and guanosine appear to have a reverse effect.
The therapeutic action, however, of the derivatives of guanylic acid have not, to the knowledge of the applicant, ever been described.
There is however a considerable, increasing need for an effective drug without side effects to treat biological disorders related to ageing.
The applicant has set out to research molecules that meet this need, and has thus been able to show that derivatives of guanylic acid can be used, among other uses, to treat these disorders and that they are non toxic.
The present invention relates to derivatives of guanylic acid according to either of the general formulae (I) and (II) in which Me is a metal trace element involved in the enzymatic activity of physiological processes, such as calcium (Ca), magnesium (Mg), copper (Cu), cobalt (Co), nickel (Ni), zinc (Zn), iron (Fe), selenium (Se), lithium (l), manganese (Mn) or any other monovalent or divalent cation chelated by guanylic acid: ##STR2##
It will be noted that in formula II the two metal substituants on the derivative may be different.
These derivatives are advantageously in the form of a microcrystalline powder that is insoluble in water. They may be used alone or in association in formulations or compositions suitable for therapeutic use.
Such compositions are preferably gastro-resistant in order to prevent hydrochloric acidity of the stomach acting on the derivatives of the invention. Such compositions may be those which comply with the standards of the French Pharmacopeia.
The derivatives may be in the form of racemic mixtures or in the form of stereo-isomers.
The present invention also relates to the hydrated forms of the above-described derivatives, in particular those in which 6 to 8 water molecules are complexed.
As a general rule, in particular at neutral pH, the derivatives of the invention are in the form of non-ionized complexes. At acid pH such complexes are likely to break up and form ionized derivatives.
The derivatives of the present invention may be prepared by solubilizing guanylic acid in a nonpolar organic solvent and adding the cation in the form of a chloride. The reaction is stoichiometric with a yield in the region of 100%. A change in colour indicates the formation of the derivatives. After eliminating the solvents, the microcrystalline powders are washed in water to eliminate the traces of cation which are unreacted. After drying, the powder has a microcrystalline form and is insoluble in water and polar solvents. The melting point of all compounds is in the region of 300.degree. C. The NMR spectrum, centesimal analysis and a single spot in thin layer chromatography confirm the structure and the purity of the derivatives obtained. Spectral X-ray analysis demonstrates that these derivatives are chelates.
The invention also relates to pharmaceutical compositions comprising at least one derivative such as described above, in conjunction with one or more diluent carriers, either excipients or additives that are compatible and pharmaceutically acceptable.
The pharmaceutical compositions of the invention are preferably in an appropriate form for administration through oral, parentera

REFERENCES:
patent: 2058180 (1936-10-01), Ruskin
patent: 3557081 (1971-01-01), Suzuki et al.
Chem. Abst. 105:201988, Campomar et al., 1986.
Chem. Abst. 103:123845, Sekine et al., 1985.
Chem. Abst. 99:176208, Kamimura et al., 1983.

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