Organic compounds -- part of the class 532-570 series – Organic compounds – Plural nitrogens bonded directly to the pteridine ring system
Patent
1997-09-25
1999-09-14
Dees, Jose' G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Plural nitrogens bonded directly to the pteridine ring system
514249, 514258, A61K 31495, A61K 31505, C07D47500
Patent
active
059524995
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a range of therapeutic compounds conjugated to one to three acyl groups derived from fatty acids. The therapeutic compounds are selected from the following group: analogues; such as adrenaline, noradrenaline and derivatives; and chlorambucil and melphalan.
In particular the present invention relates to altering the pharmacokinetic profile and mode of delivery of these therapeutic compounds by conjugating them to one to three acyl derivatives of fatty acids.
Among the most commonly used therapeutic agents are the corticosterone family of drugs based on the naturally occurring hormones produced by the adrenal cortex. There are two major groups of corticosterone hormones with overlapping activities: metabolism, possess anti-inflammatory activity at higher levels.
The corticosterones, both natural and synthetic, are based on the cholesterol molecule and generally have the common structural features of ##STR1##
These groups are generally unmodified in active analogues of the hormones with the exception of the hydroxyl moiety (alternatively described as the hydroxyl at position 21) of the hydroxyacetyl at position 17 eg hydrocortisone acetate.
An example of a glucocorticoid is hydrocortisone (cortisol or 17 hydroxy corticosterone) ##STR2## and of a mineralocorticoid is aldosterone. ##STR3##
Of particular interest in one aspect of the present invention is the anti-inflammatory action of the glucocorticoids (both natural hormones and synthetic drugs) non-limiting examples of which are:
The present inventors have shown that members of this family can be linked to one to three acyl derivatives of fatty acids. It is believed that such new conjugated compounds are improved over the unconjugated therapeutic agent. Further it is believed that these novel compounds will aid in the oral, transdermal, intraarticular, intranasal, and/or intraocular delivery of these drugs.
Accordingly in a first aspect the present invention consists in a compound of the following formula: ##STR4## in which X is a member of the corticosterone family of hormones or drugs and is linked to Y via an hydroxyl group hydrogen, methyl, ethyl or an acyl group derived from a fatty acid, with the proviso that at least one of R.sub.1, R.sub.2 and R.sub.3 is an acyl group derived from a fatty acid.
In a second aspect the present invention consists in a compound of the following formula: linked to Y via an hydroxyl group
In a third aspect the present invention consists in a method of prolonging or altering the activity of a member of the corticosterone family of hormones or drugs comprising administering the compound in the form: ##STR5## in which X is a member of the corticosterone family of hormones or drugs and is linked to Y via an hydroxyl group hydrogen, methyl, ethyl or an acyl group derived from a fatty acid, with the proviso that at least one of R.sub.1, R.sub.2 and R.sub.3 is an acyl group derived from a fatty acid.
In a fourth aspect the present invention consists in a method of prolonging or altering the activity of a member of the corticosterone family of hormones or drugs comprising administering the compounds in the form: linked to Y via an hydroxyl group
The fatty acid may be saturated or unsaturated.
As stated above X is linked via a hydroxyl group to the linker Y. Typically, this hydroxyl group will be at position 17 or 21, however it may be at other positions such as 16.
Linkers Y to join compounds with an hydroxyl group to the amino group of Tris (when B is CH.sub.2 O--R.sub.3) or the intervening amino acid (AA, if present) useful in the present invention include: the Tris (or amino acid if present) such as a dicarboxylic acid via the anhydride eg succinic anhydride, maleic anhydride. the Tris (or amino acid if present) such as glyoxylic acid (in the presence of a reducing agent eg NaBH.sub.4). the Tris (or amino acid if present) such as chloroacetic acid. to the Tris (or amino acid if present) such as ethylisocyanatoacetate.
X may be any one of the members of the corticosterone family of compounds, how
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Bender Veronika Judith
Moghaddam Minoo
Reilly Wayne Gerrard
Whittaker Robert George
Badio Barbara
Commonwealth Scientific and Industrial Research Organisation
Dees Jos,e G.
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