Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1985-08-29
1988-09-13
Lee, Mary C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514307, 514309, 514311, 514312, 514345, 514348, 514350, 514354, 514356, 514357, 514358, 546139, 546141, 546142, 546145, 546146, 546147, 546150, 546152, 546153, 546155, 546156, 546157, 546158, 546165, 546169, 546170, 546172, 546176, 546180, 546290, 546296, 546298, 546299, 546300, 546301, 546302, 546303, 546316, 546318, 546321, 546322, 546323, 546338, 546345, 546346, A61K 3144, A61K 3147, C07D21190, C07D21554
Patent
active
047710594
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to new derivatives of centrally acting amines in which a primary, secondary or tertiary amine function has been replaced with a dihydropyridine/pyridinium salt redox system. The new dihydropyridine analogues are a delivery system for the corresponding new quaternary compounds, which are pharmacologically active in vivo and are characterized by site-specific and sustained delivery to the brain.
BACKGROUND OF THE INVENTION
The delivery of drug species to the brain is oftimes seriously limited by transport and metabolism factors and, more specifically, by the functional barrier of the endothelial brain capillary wall, i.e. the blood-brain barrier or BBB. Site-specific delivery and sustained delivery of drugs to the brain are even more difficult.
Indeed, the barriers separating plasma from the brain and cerebrospinal fluid (CSF) are complex systems involving passive and active transport and subserve a number of important functions. The boundary between plasma and the central nervous system (CNS) is much less permeable than that between plasma and other tissue cells to a variety of water soluble substances, such as organic electrolytes, organic acids and bases, as well as to large molecules such as proteins. Such a barrier also provides a path for clearance from the brain of the breakdown products of cellular metabolism. The CNS and its fluids can be considered basically a three-compartment system: the blood or the plasma, CSF and brain tissue. There is a diffusion-controlled exchange between CSF and the extracellular fluid (CF) of the brain. It has also been suggested that the permeabilities of blood-CSF and blood-brain barriers are practically identical with respect to drugs and other foreign substances. Mayer et al, J. Pharmacol. and Exp. Therap., 125, 185 (1959).
The BBB is, moreover, basically the result of the fact that the endothelial cells in the brain capillaries are joined by continuous, tight intercellular junctions, such that material has to pass through the cells rather than between them in order to move from blood to brain. It is interesting that there are areas within the brain, such as the subfornical body and the postremia, in which the capillary cells are not closely linked so that they lack the characteristics of the BBB. They provide the entry of small amounts of compounds which would not ordinarily enter the barriers. Hoffman and Olszewzki, Neurology (Minneap.), 11, 1081 (1961).
Foreign compounds which enter organs other than the central nervous system with ease, may penetrate the CNS slowly or hardly at all. A number of theories concerning the nature of the barrier have been proposed. The widely accepted concept describes the boundary as a fat-like layer interspersed with small pores, although the BBB is not a simple, anatomically well-defined unitary physical entity. Shuttleworth, Prog. Exp. Tumor Res., 17, 279 (1972). Penetration of such a barrier may occur by several processes: lipid soluble substances may passively penetrate into the cells, while small molecules such as water and urea may pass through the pores. In addition to these simple physical processes, carrier-mediated and active transport processes govern the movement of many molecules through the BBB. Thus, it is generally accepted that lipid solubility, degree of ionic dissociation or protonation and the ability of temporary combination with membrane constituents affect delivery through the BBB. It has been shown, for example, that in the class of barbiturates, a quantitative correlation could be established between their ease to pass into the brain (as reflected by the different times of onset of anesthetic action) and their lipid/water partition coefficient. Mark et al, J. Pharmacol. and Exp. Therap., 123, 79 (1957). The role of lipid solubility in drug penetration through the BBB is also exemplified by the better absorption of the sparingly water-soluble thiamine propyl disulfide (TPD) as compared to the water-soluble thiamine hydrochloride (THCl). Thomson et al, Ann
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Bodor, N. et al., Pharmacelogy and Therapeutics, vol. 19, No. 3, pp. 337-386, (1983).
Breckenridge, R. J. et al., Journal of Neurochemistry, 37(4): 837-844, (1981).
Murray, W. J. et al., Chapter 8 of "Anticonvulsants", Edited by J. A. Vida, Academic Press, New York, (1977).
Chemical Abstracts 84:164580z.
Chemical Abstracts 81:20899a.
Wolff, M. E., "Burger's Medicinal Chemistry, Fourth Edition, Pt III", (1981), pp. 851-853, 877-885.
Baumeister Mary Katherine
Bjorkman Dale A.
Clarke Dennis P.
Lee Mary C.
University of Florida
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