Nervonic acid derivatives, their preparation and use

Details Nervonic acid derivatives, their preparation and use Nervonic acid derivatives, their preparation and use

2002-08-19

2003-12-16

Carr, Deborah (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Fatty compounds having an acid moiety which contains the...

C554S227000, C554S159000, C554S168000, C514S558000, C514S560000, C514S825000, C514S838000, C514S861000, C514S885000, C514S886000, C514S912000, C514S894000

Reexamination Certificate

active

06664406

ABSTRACT:

The present invention relates to certain fatty acid esters and their preparation, and to the use of such compounds or pharmaceutical formulations thereof in medicine in a mammal, including man, as, for example, anti-inflammatory or immunomodulatory agents.
Fatty acids are generally known to include the carboxylic acids that make up glycerides, such as triacylglycerols, the carboxylic esters comprised in the fat storage cells of plants and animals. Many such fatty acids are straight-chain compounds, having from three to eighteen carbon atoms (C
3
-C
18
); except for the C
3
and C
5
compounds, only acids containing an even number of carbon atoms are present in substantial amounts, due to their biosynthesis. There are both saturated and unsaturated fatty acids, such as the unsaturated C
18
oleic, &agr;-linoleic and &ggr;-linolenic (GLA) fatty acids, each having one, two and three carbon-carbon double bonds, respectively. Conventional notation therefore refers to these acids as 18:1, 18:2 and 18:3 fatty acids, respectively. The configuration about these double bonds is usually cis, which lowers the melting point of the corresponding fat (compared to the corresponding saturated and trans compounds).
Besides these short- and medium-chain fatty acids, those with longer chains, such as C
16
-C
24
, are also known and have been investigated, particularly those available from fish oils, such as eicosapentaenoic (EPA, 20:5 (n−3)) and docosahexaenoic (DHA, 22:6 (n−3)) acids, where, in (n−x), x indicates the position of the first carbon-carbon double bond with respect to the terminal methyl group on the fatty acid.
As well as their dietary metabolism and their potential dietary use, some fatty acids have been investigated in relation to medical conditions such as schizophrenia (GLA and DHA) and bipolar disorder (EPA and DHA). Some have also been proposed for improving the transport of biologically active drugs (‘bioactives’) across lipid membranes by linking the bioactive either directly or indirectly to certain fatty acids. For example, in PCT patent specification no. WO 96/34846, it is disclosed that any of the essential fatty acids (which include GLA, DHA and EPA) or any other C
12-30
fatty acid having at least two carbon-carbon double bonds may be so used. Amongst a wide range of possible bioactives and (12-30:≧2) fatty acids mentioned in that specification is specifically disclosed GLA-GLA, being a pair of GLA molecules linked via a propane-1,3-diol moiety, namely 1,3-(di-z,z,z,-octadeca-6,9,12-trienoyloxy)propane. However, no biological results in any pharmacological tests are shown for GLA-GLA, other than a report that it was administered to rats and mice up to 10 g/kg without evidence of diarrhea (ie absence of toxicity, rather than presence of therapeutic effect).
Nevertheless, GLA-GLA is mentioned as one possible propane-1,3-diol compound having a broad range of listed uses, including the treatment of inflammatory diseases. However, as reported hereinbelow with particular reference to Example 4, we found that GLA:GLA had no effect in our tests for anti-inflammatory activity. Accordingly, it might be expected that other combinations of (12-30:≧2) fatty acids linked via a propane-1,3-diol moiety might also not show anti-inflammatory action, especially where such action was not already demonstrated for at least one of the fatty acid moieties involved.
Furthermore, no possibility of using other types of fatty acids, such as those having only one carbon-carbon double bond, is contemplated in WO 96/34846. One such different type of fatty acid is nervonic acid. Nervonic acid (24:1 (n−9)) is cis (or z)-tetracos-15-enoic acid; it is not classed as an essential fatty acid and has only one unsaturated C═C bond. It plays a part in the biosynthesis of myelin and is one of the major fatty acids in brain sphingolipids. Nervonic acid has therefore been implicated in diseases involving demyelination, such as adrenoleukodystrophy (ALD) and multiple sclerosis (MS). It has therefore been proposed to administer nervonic acid or a source thereof as a pharmaceutical formulation thereof to patients suffering from demyelinating conditions (as described in PCT published specification no. WO 91/07955), or to provide nervonic acid or a functional derivative thereof as a dietary supplement, for example, as baby or infant feeds, or to pregnant or lactating women (as described in PCT published specification no PCT/GB95/01985). Although the precise causes of MS are not yet known, strong evidence now suggests that MS results from an autoimmune process triggered by an environmental factor, possibly a non-specific viral infection, in a genetically susceptible individual, in which immune cells mistake myelin as a foreign invader and attack it. This process produces perivascular inflammation in the CNS and eventually damages not only myelin but also underlying nerve tissue. However, nervonic acid is not known to have any general effect on inflammation or inflammatory diseases.
As a result of damage to the myelin and nerve tissue, the blood-brain barrier is disrupted, enabling activated T-cells to enter the brain and recruit other lymphocytes. Activated T-cells release lymphotoxin, interferon gamma (IFN-&ggr;) and other inflammatory cytokines. Lymphotoxin can damage oligodendrocytes, and IFN-&ggr;, which has been shown to provoke MS exacerbations, stimulates the immune system in a number of ways thought to aggravate MS. Oligodendrocyte cells synthesise myelin-specific proteins and lipids, and their role is critical for both normal myelin sheath formation and normal brain function.
For example, IFN-&ggr; augments expression of major histocompatibility complex (MHC) class II molecules on macrophages, and induces their expression on astrocytes, microglia and endothelial cells. Antigenic myelin peptides associated with these MHC molecules are recognised by T-cells, which proliferate in response to antigen presentation, amplifying the immune response.
Macrophages activated by IFN-&ggr; also release tumour necrosis factor (TNF), which has been shown to damage oligodendrocytes in vitro. In addition, cytokines, proteinases and lipases are secreted, and B-cells are induced to synthesise antibodies. This response results in demyelination and gliosis, which causes nerve impulses to be slowed or halted and produces the symptoms of MS.
It has now surprisingly been found that certain derivatives of nervonic acid possess anti-inflammatory and/or immunomodulatory activity. Furthermore, some of these derivatives assist in the passage of nervonic acid across the blood-brain barrier.
Accordingly, the present invention provides a compound of formula (I):
wherein R is hydrogen (H) or a residue of a carboxylic acid or a salt of the compounds where R is H.
The definition of formula (I) also includes, where applicable, individual isomers and mixtures thereof; and derivatives (especially bioprecursors or pro-drugs) thereof.
The term “bioprecursor” or “pro-drug” means a pharmacologically acceptable derivative—eg an ester (such as a biolabile ester derivative of a —COOH group)—that is converted in vivo to a compound of the present invention. Suitable pro-drugs can be determined by reference to Goodman and Gilman, The Pharmacological Basis of Therapeutics, 8th Edition, McGraw-Hill, Int. Ed. 1992, particularly “Biotransformation of Drugs”, pp. 13-15.
The carboxylic acid referred to in the definition of R preferably has from 1 to 26 carbon atoms, and may be straight- or branched-chain, saturated or unsaturated. More preferably, the carboxylic acid is straight chain and is selected from the group consisting of mono- and poly-unsaturated fatty acids. Particularly preferred are compounds of formula (I) wherein R is a residue of a C
18
to C
24
mono- or poly-unsaturated fatty acid, having from 1 to 6 carbon-carbon double bonds. Especially preferred is when R is a residue of nervonic acid (24:1(n−9)), docosahexaenoic acid (22:6(n−3)) or &ggr;-linolenic acid (18:3(n−6)), where x in (n−x)

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