Polyunsaturated fatty acid derivatives and their use

Details Polyunsaturated fatty acid derivatives and their use Polyunsaturated fatty acid derivatives and their use

1999-12-21

2001-08-14

Carr, Deborah D. (Department: 1621)

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

Organic compounds

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

C554S036000, C554S080000

Reexamination Certificate

active

06274747

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel polyunsaturated fatty acid derivatives and their use as therapeutic agents.
BACKGROUND OF THE INVENTION
Amides of fatty acids (saturated and unsaturated) having the following formula:
R—CO—NH
2
wherein the R is alkyl residue of fatty acid, represent a new group of lipid bioregulators originated from long-chain fatty acids via amidation by corresponding amines. Erucamide (13-docosenamide) was found to be the major bovine mesentery angiogenic lipid. The mechanism of angiogenic activity is unknown and this lipid does not promote proliferation of endothelial cells or induce inflammatory effects (Wakamatsu K. et al., Biochem. Biophys,. Res. Commun., V.168. p. 423-429, 1990). A molecule isolated from the cerebrospinal fluid of sleep-deprived cats has been chemically characterized and identified as cis-9,10-octadecenoamide. Other fatty acid primary amides in addition to cis-9,10-octadecenoamide were identified as natural constituents of the cerebrospinal fluid of cat, rat and human, indicating that these compounds compose a distinct family of brain lipids. Synthetic cis-9,10-octadecenoamide induced physiological sleep when injected into rats. Together, these results suggest that fatty acid primary amides may represent a previously unrecognised class of biological signal molecules (Cravatt B. F. et al., Science., V.268., P.1506-1509, 1995).
A very thoroughly investigated group of compounds are ethanol amides of fatty acids, having the following formula:
R—CO—NH—CH
2
CH
2
—OH
where R is an alkyl residue of a fatty acid.
Ethanol amides of fatty acids bound with cannabinoid receptors in the central nervous system or in peripheral tissues are considered as endogenous ligands for these receptors. They exhibit pharmacological patterns like cannabimimetics (Bezuglov V. V. et al. Biochemistry (Moscow). V.63, N 1. P. 27-37,1998).
Amides of retinoic acid (cis-trans isomers) with some amino acids having the following formula:
R—CO—NH—Y—COOH
wherein R is an alkyl residue of retinoic acid and Y is a residue of amino acid have been synthesised via all-trans-retinoyl chloride and an ester of the amino acid (Shealy Y. F. et al., J.Med.Chem. V.31.,P.190-196, 1988). The retinoyl derivatives of leucine, phenylalanine, alanine, tyrosine and glutamic acid were prepared. The 13-cis-retinoyl derivatives of leucine, phenylalanine, alanine, and glycine were prepared similarly from 13-cis-retinoic acid. In assays of the retynoylamino acids for reversal of squamous metaplasia in hamster trachea organ cultures, these compounds were less active than retinoic acid, but the leucine, alanine and phenylalanine derivatives were similar in activity to several retinamides that suppress bladder carcinogenesis in vivo. Two of the retinoylamino acids, as well as two simple retinamides were shown to be moderately cytotoxic to murine leukemia and human epidermoid carcinoma cells in culture.
One problem addressed by the present invention is that of making available novel compounds for use in the manufacture of pharmaceuticals, e.g. for the treatment of cancer and immune deficiencies, said compounds exhibiting i.a. higher activity than presently known compounds.
SUMMARY OF THE INVENTION
The present invention makes available novel amides according to the attached claims, in particular amides of the all-trans-retinoic acid or 13-cis-retinoic acid and arachidonic acid and docosahexaenoic acid and eicosapentaenoic acid or linoleic acid with 2-aminoethanol, alpha-L-serine, alpha-L-threonine, alpha-L-tyrosine containing phosphate groups. Further, the present invention discloses the use of these compounds, in particular their pharmaceutical application as specified in the attached claims.
The structure of these compounds is covered by the following general formula:
 R—CONH—X—OPO(OH)
2
wherein
R is
or
CH
3
(CH
2
)
4
(CH══CH—CH
2
)
4
CH
2
CH
2
—
or
CH
3
(CH
2
CH══CH)
6
CH
2
CH
2
—
or
CH
3
(CH
2
CH══CH)
5
(CH
2
)
3
—
or
CH
3
(CH
2
CH══CH)
3
(CH
2
)
7
—
and X is
—CH
2
—CH
2
—
or
—CH(CO
2
H)—CH
2
—
or
—CH(CO
2
H)—CH(CH
3
)—
or
—CH(CO
2
H)—CH
2
—C
6
H
5
—
Thus the amino group of 2-aminoethanol or the alpha-amino group of amino acid forms an amide bond with the carboxylic group of arachidonic acid, docosahexaenoic acid, eicosapentaenoic acid or linoleic acid and all-trans-retinoic acid or 13-cis retinoic acid. At the same time the hydroxyl group of 2-aminoethanol and the amino acid is modified by a phosphate residue. The compounds can be applied as immunostimulating therapeutical agents for the treatment of immune-deficiencies.
DESCRIPTION OF THE INVENTION
The novel compounds according to the present invention are amides of all-trans-retinoic acid or 13-cis-retinoic acid and arachidonic acid and docosahexaenoic acid and eicosapentaenoic acid or linoleic acid with 2-aminoetanol, alpha-L-serine, alpha-L-threonine, alpha-L-tyrosine. At the same time hydroxyl groups of amino acids and 2-aminoethanol are modified by phosphate residues. The all-trans-retinoic acid or 13-cis retinoic acid and arachidonic acid and docosahexaenoic acid and eicosapentaenoic acid or linoleic acid have been derived by various procedures from naturally-occurring products. It is however possible, within the scope of the present invention, to produce these compound synthetically.
The main characteristic among the novel synthesised compounds is the phosphorylation of the hydroxyl groups of N-acyl derivatives of amino acids and 2-aminoethanol.
Retinoic acid derivatives according to the present invention include the following compounds:
1. N-(all-trans-retinoyl)-o-phospho-2-aminoethanol
1a. N-(13-cis-retinoyl)-o-phospho-2-aminoethanol
2. N-(all-trans-retinoyl)-o-phospho-L-serine
2a. N-(13-cis-retinoyl)-o-phospho-L-serine
3. N-(all-trans-retinoyl)-o-phospho-L-threonine
3a. N-(13-cis-retinoyl)-o-phospho-L-threonine
4. N-(all-trans-retinoyl)-o-phospho-L-tyrosine
4a. N-(13-cis-retinoyl)-o-phospho-L-tyrosine
Arachidonic acid derivatives according to the present invention include the following compounds:
5. N-arachidonoyl-o-phospho-2-aminoethanol
6. N-arachidonoyl-o-phospho-L-serine
7. N-arachidonoyl-o-phospho-L-threonine
8. N-arachidonoyl-o-phospho-L-tyrosine
Docosahexaenoic acid derivatives according to the present invention include the following compounds:
9. N-docosahexacnoyl-o-phospho-2-aminoethanol
10. N-docosahexaenoyl-o-phospho-L-serine
11. N-docosahexaenoyl-o-phospho-L-threonine
12. N-docosahexaenoyl-o-phospho-L-tyrosine
Eicosapentaenoic acid derivatives according to the present invention include the following compounds:
13. N-eicosapentaenoyl-o-phospho-2-aminoethanol
14. N-eicosapentaenoyl-o-phospho-L-serine
15. N-eicosapentaenoyl-o-phospho-L-threonine
16. N-eicosapentaenoyl-o-phospho-L-tyrosine
Linoleic acid derivatives according to the present invention include the following compounds:
17. N-linolenoyl-o-phospho-2-aminoethanol
18. N-linolenoyl-o-phospho-L-serine
19. N-linolenoyl-o-phospho-L-threonine
20. N-linolenoyl-o-phospho-L-tyrosine
The structural formulas of these compounds are presented below:
In developing the scheme of synthesis the present inventor took into account the following properties of the title compounds:
i) a high degree of unsaturation
ii) presence of an asymmetric centre
iii) presence of sufficiently labile groups e.g. amide and phosphate.
Many of the well-known methods of acylation and phosphorylation could therefore not be used for the synthesis of such compounds. The preparation of the mixed carbonic carboxylic anhydrides followed by acylation of amino moiety of the methyl esters of hydroxyamino acids and ethanolamine was carried out at low temperature. The method of synthesis developed by the present inventor enables the N-acyl derivatives to be obtained with nearly quantitative yields. It is demonstrated that beta-cyanoethyl phosphate is a universal phosphorylation agent for hydroxyamino acids containing primary, secondary or aromatic OH-groups. Beta-cyanoethyl and ester protective groups were removed simultaneously by mild alkaline hydrolys

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