Use of N-acyl derivatives of aminoalcohols in the manufacture of

Details Use of N-acyl derivatives of aminoalcohols in the manufacture of Use of N-acyl derivatives of aminoalcohols in the manufacture of

1996-09-23

1999-07-20

MacMillan, Keith D.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

514625, A61K 31155

Patent

active

059256788

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to the use of N-acyl derivatives of aminoalcohols with mono and dicarboxylic acids for the prevention and treatment of neuropathological states connected with excitotoxicity.


PRIOR ART DISCLOSURE

Recent research has established that the nervous system is not an isolated entity but a component of a complex intercommunication system together with the main homeostatic systems--immune system and endocrine system--where stimuli from one of the three systems are received and adaptive responses are processed by the other two in order to maintain or regulate homeostatic equilibrium in the body. In fact, although the nervous system, the endocrine system and the immune system utilize languages of their own, they can translate and process the messages received from the other systems.
Scientific literature has recently reported some results suggesting that the mast cell, an immunocompetent cell ubiquitously present in tissues, might be the element providing communication between the three systems: due to the anatomic dislocation--in proximity of nerve endings and in contiguity with the vascular system--and to its functional role being evidenced, said cell might be capable of acting as a "gate keeper" within said complex system.
Following tissue injury, stimuli capable of activating mast cells are produced leading to the prompt release from preformed stores of mediators and other substances with chemotactic, proinflammatory and cytotoxic effects. Cytokines (TNF-.alpha. and interleukins), vasoactive amines (serotonin, bradikinin and histamine), heparin and PAF are some examples.
The presence of mediators and kinins at the site of injury increases the sensitivity to pain in the acute stage; further, the accumulation of IL-1, IL-3 and TNF-.alpha. induces the synthesis of NGF which locally increases the proinflammatory agonist stimulus (mast cell and T-lymphocyte proliferation, mast cell degranulation), which is thus amplified and prolonged (U. Otten et al., 1989, "Nerve Growth Factor induces growth and differentiation of human lymphocytes", PNAS 86: 10059-10063; J. S. Marshall et al., 1989, "The role of mast cell degranulation product in mast cell hyperplasia", The J. of Immunology, 144: 1886-1892) having the consequence of inducing modifications in the number of nerve endings and facilitate these inflammatory conditions to become chronic (R. Dubner and M. A. Ruda, 1992, "Activity-dependent neuronal plasticity following tissue injury and inflammation", TINS, 15, 3: 96-103).
These and further evidences for the susceptibility and rapidity of mast cell degranulation phenomena suggested the need for an inhibitory control. In addition to the corticosteroid-mediated pleiotropic control, already characterized, a local control system has been developed by the Applicant, said system being pharmacologically applicable with specific compounds structurally related to endogenous autacoids and chemically definable as N-acyl lipids, as disclosed in European patent applications No. 92121862.4 published with No. 0 550 006 A3 and No. 92121864.0 published with No. 0 550 008 A2.
The experimental evidence obtained by the Applicant for these N-acyl lipids proved the presence of a local antagonist endogenous regulation mechanism, meant to control mast cell degranulation induced by neurogenic and immunogenic supramaximal stimuli (ALIA=Autacoid Local Inflammation Antagonism). Said discovery is of great pharmacological importance, making it possible to synthesize drugs, chemically definable as N-acyl derivatives of mono and polycarboxylic acid with aminoalcohols, which can act as autacoids with the ability to modulate mast cell activation associated to neuroimmunogenic inflammatory processes in autoimmune diseases and other pathological conditions (see the aforementioned patent applications).


SUMMARY OF THE INVENTION

The Applicant has surprisingly found that compounds belonging to the class of N-acyl derivatives of mono and dicarboxylic acids with aminoalcohols which can exert a protectiv

REFERENCES:
patent: 5227397 (1993-07-01), Saccomano et al.
patent: 5618842 (1997-04-01), Della Valle et al.
John W. Olney "Excitotoxic Amino Acids and Neuropsychiatric Disorder" 1990, pp. 47-71.
R. Dubner et al. "Activity-Dependent Neuronal Plasticity Following Tissue Injury and Flammation." 1992 pp. 96-103.
Uwe Otten eual. "Nerve Growth Factor Induces Growth and Differentiation of Human B Lynphocytes ." Dec. 1989, pp. 10059-10063
Jean S. Marshall et al. "The Role of Mast Cell Degranulation Products in Mast Cell Hyperplasia" Mar. 1, 1990., pp. 1886-1892.
Anthony N. Van Den Pol et al. "Glutarnate Neurons in Hypothalamus Regulate Excitatory Transmission" Jul. 1993, 2829-2838.
Melvyn P. Heyes, PhD, et al ., Quinolinic Acid in Cerebrospinal Fluid and Serum HIV-1 Infection Relationship to Clinical and Neurolgical Status Aug. 26, 1990, pp. 202-209.

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