Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1995-03-09
1996-09-17
Spivack, Phyllis G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
A61K 3166
Patent
active
055568432
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP 93/02061, filed Aug. 2, 1993.
BACKGROUND AND SUMMARY OF THE INVENTION
The present invention concerns the therapeutic use of phosphoryl-L-serine-N-acyl-sphingosine composed of a mixture of compounds of formula I or II, ##STR1## in which n is an integer of 6-16 and R means an acyl residue of a higher aliphatic acid having between 16 and 24 carbon atoms, the distribution of the values for n and R being those of a natural spingomyelin. The invention also includes a new process for the preparation of these compounds, as well as pharmaceutical preparations containing said compounds as active ingredients. The ratio of the mixture of compounds of formulas (I) and (II) is not critical in order to use the compound of the present invention. The compound, as previously defined, was prepared by treatment with phospholipase D, as described in Biochemistry vol. 28, No. 8, 1989, 34-57, starting from a derivative of spingomyelin (i.e. phosphorylcholine-N-acyl-sphingosine, in which the acyl group was derived from higher aliphatic acids of different molecular size and was variable between C12 and C24), and particularly to an analog of a spingomyelin having an acyl group derived from 4-doxyl-pentanoic acid on the sphingosine amino group instead of the acyl residue R. In the cited paper there are no indications about pharmacological properties of the derivatives.
DETAILED DESCRIPTION OF THE INVENTION
It has now been found that the compound has various interesting pharmacological properties and can be used therapeutically, especially in human medicine. More precisely the phosphoryl-L-serine-N-acyl-sphinogosine of the present invention has an inhibiting action on the activation of protein kinase C, which, activation can be undesired or have negative effect, in particular conditions of unbalance of the normal mechanisms of neurotransmittal functions. Activation is caused by an increased concentration of excitatory amino acids, like glutamic and/or aspartic acid; these acids have a direct toxic action on neuronal cells in the above mentioned abnormal conditions.
Phosphoryl-L-serine-N-acyl-spingosine can therefore be used in the therapy of many diseases of the central nervous system, as those arising after cerebral degenerations or lesions, like ischaemia, hypoxia, epilepsy, traumas and compressions, metabolic dysfunctions, aging, toxic-infective and chronic degenerative diseases, like Alzheimer's, Parkinson's and Huntington's diseases.
Phosphoryl-L-serine-N-acyl-sphingosine is moreover able to increase glycemia and histamine levels, resulting in cerebral glucose accumulation, which has important reflexes in the functionality of CNS. Also an activating influence on cerebral neurotransmitter systems was shown, particularly at the cholinergic level, the compounds of the present invention can increase the release of acetylcoline (ACh) in the cerebral cortex area. The action on the cholinergic system is also reinforced by the efficacy of the aforesaid compounds in influencing cognitive functions, like e.g. learning and memorizing, in various behavioral tests (e.g. the capacity to invert scopolamine caused amnesia). The compounds I and II can also be used in therapies associated with slowdown of cerebral metabolism, in involutive cerebral syndromes of different origins (due e.g. to senile decay and/or vascular pathologies), in Alzheimer's disease, memory loss and senile dementia, anoxic and edematous conditions, cerebral tiredness, chronic vascular cerebropathies of aging, and pre-senile dementia following trauma, postanoxic cerebropathies and extrapyramidal syndromes. Moreover the compounds of the present invention perform a modulatory action on the immune system and, particularly, an inhibitory action on the secretion of TNF (tumor necrosis factor). They can therefore be favorably used in the therapy of pathologies characterized by a modified immunological reactivity and/or by autoimmunological symptoms like multiple sclerosis, cachectic situations associated with infections and neoplastic dis
REFERENCES:
JP 1135720 Abstract (Derwent) 29 May 1989.
Kirschner Gunter
Menon Gianpaolo
Romeo Aurelio
Fidia S.p.A.
Spivack Phyllis G.
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