N′N′-dichlorinated omega-amino acids and uses...

Details N′N′-dichlorinated omega-amino acids and uses... N′N′-dichlorinated omega-amino acids and uses...

2000-09-26

2002-09-17

Russel, Jeffrey E. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S114000, C514S558000, C514S561000, C514S578000, C530S300000, C554S103000, C554S114000, C562S011000, C562S104000

Reexamination Certificate

active

06451761

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to methods of modifying amino acids, small peptides, or other primary amines, so that they are able to cross the blood-brain barrier and reach the central nervous system, and products of such methods. In particular, this invention relates to dichlorination of omega-amino acids such as taurine, homotaurine, and GABA, to allow them to cross the blood-brain barrier and reach the central nervous system.
BACKGROUND OF THE INVENTION
The &ohgr;-amino acids are a group of substances consisting of a terminal unsubstituted amino group and an acidic (phosphonic, sulphonic, sulphinic or carboxyl) group separated by an aliphatic (unbranched) carbon chain (NH
2
(CH
2
)
n
SO
3
H
2
, —PO
3
H, SO
2
H
2
, or NH
2
(CH
2
)
n
COOH; n=1-5). Some of these amino acids are formed in vivo from the enzymic &agr;-decarboxylation of the corresponding &agr;-amino-&agr;-carboxyl amino acid: glutamate/&ggr;-aminobutyric acid (GABA), cysteic acid/taurine, homocysteic acid/homotaurine. Although evidence for the existence in tissues of a number of such decarboxylases is quite convincing (Abbott et al., 1981; Almarghini et al., 1991; Huxtable and Lippincott, 1982; Irving et al., 1986), the in vivo synthesis of taurine nevertheless appears marginal despite its presence in &mgr;molar concentrations in many organs, notably brain, heart and skeletal muscle (Guilarte, 1989; van Gelder and Bélanger, 1988), while homotaurine may only exist as traces in the body. In human and several other mammalian species, especially carnivores, taurine appears mostly to derive from nutrition; in herbivores it originates from synthesis by enteric bacteria, while the origin of the very high concentrations of taurine in invertebrate tissues and body fluids is not yet entirely clear. In contrast, neural tissue, especially, is rich in glutamic acid decarboxylase and several isoforms have been identified, with different affinities for their co-factors such as pyridoxal phosphate (vitamin B
6
) (Martin and Rimvall, 1993). Practically all GABA present in neural tissue can be accounted for by &agr;-decarboxylation of glutamic acid which, in turn, originates entirely from in situ synthesis within the CNS. Finally, L-leucine, an &agr;-amino acid, belongs to the group of amino acids which need to be supplied by the diet, and thus is classified as an (nutritionally) essential amino acid.
Both taurine and GABA have been demonstrated in the past 30 years to be essential for normal functioning of the central nervous system (CNS). GABA is now known to represent the principal inhibitory transsynaptic messenger substance in the CNS (Elliott and Florey, 1956; Kravitz et al., 1962). Many CNS dysfunctions marked by excessive synchronized neuronal discharge can be traced back to either an imbalance between the excitatory action of glutamic acid mediated transmitter function and the inhibitory effect of GABA, or to a direct failure in GABAergic inhibition, or to both conditions simultaneously. Because of the intimate precursor-product relationship between glutamic acid and GABA, failure in one transmitter system will eventually always cause secondary modification of the other (Hamberger and van Gelder, 1993). Important disorders of brain function in which an aberration of the glutamate-GABA balance is implicated include, among others, most forms of epilepsy, intractable pain disorders and Huntington's Disease.
As opposed to the glutamate-GABA system which at any one moment directly determines the excitation-inhibition balance in a particular brain region, taurine appears to exert a more tonic influence on the operations of the CNS. By a continuous redistribution of taurine between the intracellular and extracelluar spaces via a series of uptake and release mechanisms, as well as by ongoing readjustment of the amount of taurine free in the cytoplasm and that sequestered (i.e., bound) in some form within the cell, taurine controls or prevents excessive fluctuations in the volume of the cerebral spinal fluid (CSF) and of the water content within neural tissue (van Gelder, 1989; van Gelder, 1990). Changes in the dimensions of the intercellular spaces, as well as in the volumes of neurons and apposing glial cells, are a consequence of water redistribution which occurs proportionally to neural tissue discharge rates and the accompanying changing rates of energy metabolism: glucose to ATP, CO
2
and water. Taurine thus functions as the principal osmol to counteract such volume changes, a role probably related to its very slow or, indeed, absence of metabolic transformation. Either in addition to this osmotic role of taurine in the CNS and, probably, other organ tissues such as heart and skeletal muscle, or as a consequence of this function, taurine exerts a strong regulation on the intracellular ratio of free to sequestered calcium. The amount of calcium as the free ion in the cytoplasm of a neuron is a key determinant of neuronal excitability and discharge patterns.
Ratios of taurine/glutamate neural tissue contents and blood concentrations are remarkably stable in various species and changes in these ratios are often found in association with a number of severe disorders such as epilepsy, infant malnutrition, and cerebral trauma (Armstrong, 1973; Chesney, 1988; Räihä et al., 1976; van Gelder, 1972). Furthermore, in such circumstances absolute taurine levels are often found decreased, which, in light of the very constant and species characteristic organ content of taurine normally observed, suggests an important malfunction of a major homeostatic mechanism.
SUMMARY OF THE INVENTION
In accordance with a broad aspect of the invention there is provided a method of treating a CNS disorder in a subject in need of such treatment, the method comprising administering to the subject an effective amount of an N′N′-dichlorinated amino acid, peptide, peptidomimetic, amine, or a pharmacologically acceptable analogue or derivative thereof, such that a CNS disorder is treated. The method may include administering to the subject an effective amount of an N′N′-dichlorinated amino acid, or a pharmacologically acceptable analogue or derivative thereof, of the general formula I:
wherein R is a phosphonic, sulphonic, or carboxyl group, and n is an integer selected such that the biodistribution of the compound for an intended target site is not prevented while maintaining the activity of the compound. According to the method of the invention, n may be an integer from 1 to 10; preferably, n may be an integer from 1 to 5. In certain embodiments, the invention provides a peptide wherein a compound of formula I is the N-terminal residue. In a preferred embodiment of the invention, the amino acid is &ohgr;-amino acid selected from the group consisting of taurine, homotaurine, &ggr;-aminobutyric acid, &bgr;-alanine, and analogues and derivatives thereof.
The method of the invention may be used to treat a CNS disorder characterized by an abnormality in the profile of one or more amino acids or associated with excessive synchronized neuronal discharge. In various embodiments, the method of the invention may be used to treat an abnormality which is an imbalance in the ratio of taurine and glutamate, or a CNS disorder characterized by an imbalance between the excitatory activity associated with glutamic acid and the inhibitory activity associated with GABA, by a direct failure in GABAergic inhibition, or by both. The method of the invention may be used to treat such CNS disorders as epilepsy, intractable pain disorders, Huntington's Disease, Parkinson's Disease, and abnormalities associated with CNS trauma. The method of the invention may also be used to treat a tumour or a CNS disorder associated with infant malnutrition.
By another broad aspect of the invention, there is provided an N′N′-dichlorinated amino acid, peptide, peptidomimetic, or amine capable of crossing the blood-brain barrier of a subject when administered thereto. The invention may provide an N′N′-dichlorinated

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