Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1999-02-05
2000-03-28
Criares, Theodore J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514616, 514647, A61K 31135, A61K 3116
Patent
active
060432853
DESCRIPTION:
BRIEF SUMMARY
The present invention concerns the use of p-aminophenol derivatives for the preparation of pharmaceutical compositions useful in the treatment of neurodegenerative diseases.
More particularly, the present invention concerns the use of derivatives of p-aminophenol and prodrugs thereof for the preparation of pharmaceutical compositions useful in the treatment of neurodegenerative diseases which contain an inflammatory component with production in loco of inflammatory markers such as proteins of the complement and cytokines.
Still more particularly, the present invention concerns the use of compounds having the formula ##STR1## wherein R.sub.1 is hydrogen or lower acyl, and
Typical examples of such compounds are phenacetin (R.sub.1 .dbd.COCH.sub.3 ; R.sub.2 .dbd.C.sub.2 H.sub.5), also known as acetophenetidine, and paracetamol (R.sub.1 .dbd.COCH.sub.3 ; R.sub.2 .dbd.H), also known as acetaminophen or N-acetyl-p-aminophenol.
Typical examples of prodrugs are propacetamol (B. Bannwarth et al., "Br. J. Clin. Pharmac.", 34, 79-81, 1992), acetaminosalol (R. Q. Brewster, "J. Am. Soc.", 40, 1136, 1918) and its glycine ester (I. M. Kovach et al., "J. Pharm. Sci.", 64, 1070, 1975). With regard to use of the term "prodrug", the reader is referred to "Burger's Medicinal Chemistry and Drug Discovery--Vol. 1; Principles and Practice--5th ed.--Ed. Manfred E. Wolff--pp. 172-178".
It is already known that these compounds possess analgesic and antipyretic actions comparable to those of aspirin, whilst unlike acetylsalycylic acid they possess no significant anti-inflammatory action (Insel A. P. in: "The Pharmacologic basis of therapeutics" Goodman Gilman A. et al. ed., pp. 656-659, Pergamon Press, 1990).
Because of its general toxicity and side effects, phenacetin is currently little used for therapeutic purposes.
Paracetamol however is well tolerated and presents no significant side effects in low therapeutic doses from 0.5 to 1 g, 3 or 4 times a day.
Paracetamol is rapidly absorbed and is distributed evenly throughout the major part of the tissues of the organism, including the brain. The plasma concentration reached within a few minutes of oral administration of 1 g paracetamol is approximately 10 mg/l (66.2 .mu.M) and increases to approximately 1.5 mg/l after 6 hours. The tissue concentration is substantially the same as the plasma concentration (Prescott L. F., "Br. J. Clin. Pharmacol.", 10 (suppl. 2), 291-298S, 1980).
The mode of action of paracetamol is not yet fully known. It is however generally agreed that its activity is dependent on its ability to inhibit prostaglandin production mainly in the central nervous system. This action would appear to explain the analgesic and antipyretic effects of paracetamol. The absence of action on peripheral cycloxygenase could, on the other hand, be responsible for its lack of anti-inflammatory action (Clissold, S. P., "Drugs", 32 (suppl. 4), 46-59, 1986).
Alzheimer's disease is a pathology characterised by progressive neurodegeneration leading to dementia. Autopsy examination constantly reveals certain typical histological markers such as plates due to excessive deposition of .beta.-amyloid and loss of neurons and/or synapses (Selkoe D. J. et al., "Neuron", 6, 487-493, 1991).
In recent years the presence of inflammation markers in cerebral samples from patients suffering from Alzheimer's disease has been documented with increasing frequency. Proteins typical of inflammatory processes such as antigens of histocompatibility, certain cytokines and their receptors, Fc receptors, certain proteins of the acute phase and proteins of the classic pathway of activation of the complement together with their receptors have in fact been identified in amyloid plates or in the region of such plates (Dickson D. W. et al., "Glia", 7, 75-83, 1993). It has also been demonstrated that such inflammatory proteins are secreted in loco by glial cells and microglial cells (Hugh Perry V. et al., "Trends Neurol. Sci.", 7, 268-273, 1993). A minor incidence of this pathology in patients suffering from rheumato
REFERENCES:
patent: 5643960 (1997-07-01), Breitner et al.
patent: 5756548 (1998-05-01), Flitter et al.
Martindale, The Extra Phamacopoeia, Thirtieth Edition, pp. 2, 27-28 (1993).
Neurobiology of Aging, vol. 16 (4), pp. 523-530; J.C.S. Breitner et al. (1995).
Brufani Mario
Milanese Claudio
Pinza Mario
Angelini Ricerche S.p.A. Societa'Consortile
Criares Theodore J.
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