Therapeutic compound—fatty acid conjugates

Details Therapeutic compound—fatty acid conjugates Therapeutic compound—fatty acid conjugates

1999-04-12

2001-08-28

Badio, Barbara P. (Department: 1616)

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

Organic compounds

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

Reexamination Certificate

active

06281376

ABSTRACT:

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:
1. the corticosterone family of drugs;
2. opioids and opioid antagonists;
3. antiviral nucleosides, such as AZT;
4. cyclosporins and related cyclopeptides;
5. folate antagonists including methotrexate, folic acid and folic acid analogues;
6. catecholamine precursors, such as DOPA and Dopamine, and catecholamines, such as adrenaline, noradrenaline and derivatives; and
7. alkylating agents containing a carboxylic acid group, such as 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.
1. The Corticosterone Family of Drugs
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:
glucocorticoids—normal biological action is the regulation of carbohydrate metabolism, possess anti-inflammatory activity at higher levels.
mineralocorticoids—concerned with water and mineral metabolism.
The corticosterones, both natural and synthetic, are based on the cholesterol molecule and generally have the common structural features of:
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.
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:
cortisone
hydrocortisone
fludrocortisone
prednisone
prednisolone
methylprednisolone
triamcinolone
dexamethasone
betamethasone
paramethasone
fluocinolone
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:
in which X is a member of the corticosterone family of hormones or drugs and is linked to Y via an hydroxyl group
Y is a spacer group
AA is an amino acid; n is a number from 0 to 5
B is H or CH
2
O—R
3
R
1
, R
2
and R
3
are the same or different and are either hydrogen, methyl, ethyl or an acyl group derived from a fatty acid, with the proviso that at least one of R
1
, R
2
and R
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:
X—Y—[AA]
n
—NH—CH
2
—CH
2
O—R
4
in which X is a member of the corticosterone family of hormones or drugs and is linked to Y via an hydroxyl group
Y is a spacer group
AA is an amino acid; n is a number from 0 to 5, and
R
4
is an acyl group derived from a fatty acid.
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:
in which X is a member of the corticosterone family of hormones or drugs and is linked to Y via an hydroxyl group
Y is a linker group
AA is an amino acid; n is a number from 0 to 5
B is H or CH
2
O—R
3
R
1
, R
2
and R
3
are the same or different and are either hydrogen, methyl, ethyl or an acyl group derived from a fatty acid, with the proviso that at least one of R
1
, R
2
and R
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:
X—Y—[AA]
n
—NH—CH
2
—CH
2
O—R
4
in which X is a member of the corticosterone family of hormones or drugs and is linked to Y via an hydroxyl group
Y is a spacer group
AA is an amino acid; n is a number from 0 to 5, and
R
4
is an acyl group derived from a fatty acid.
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
2
O—R
3
) or the intervening amino acid (AA, if present) useful in the present invention include:
a) a linker with a carboxyl group to the compound and a carboxyl group to the Tris (or amino acid if present) such as a dicarboxylic acid via the anhydride eg succinic anhydride, maleic anhydride.
b) a linker with a carboxyl group to the compound and an aldehyde group to the Tris (or amino acid if present) such as glyoxylic acid (in the presence of a reducing agent eg NaBH
4
).
c) a linker with a carboxyl group to the compound and an halide group to the Tris (or amino acid if present) such as chloroacetic acid.
d) a linker with a carboxyl group to the compound and a N═C═O group 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, however, it is presently preferred that X is hydrocortisone or cortisone.
In further preferred embodiments of this aspect of the present invention Y is a dicarboxylic acid, AA is not present or is glycine or alanine and the linkage is via the hydroxyl group at position 21.
As will be appreciated R
1
, R
2
and R
3
are either hydrogen or an acyl group of a fatty acid. Also it is clear to those skilled in the art that substitutions other than methyl or ethyl are possible at R
1
, R
2
and R
3
. The prime requirement is that at least one of R
1
, R
2
and R
3
is an acyl group derived from a fatty acid.
When R
1
, R
2
and R
3
are each acyl groups of fatty acids it is preferred that they are the same group. It is also preferred that the acyl groups of fatty acids have a carbon chain of 3 to 18, more preferably 10 to 18.
It will be appreciated by those skilled in the art that similar modifications could be made to some members of the other classes of steroid (or analogues) hormones such as the male and female sex hormones at hydroxyl groups situated at various sites in the molecule.
The present invention also provides therapeutic compositions comprising the compound of the first or second aspect of the present invention and a pharmaceutically acceptable carrier. The composition may further include an unconjugated member of the corticosterone family of hormones or drugs.
The therapeutic composition may be administered by any appropriate route as will be recognised by those skilled in the art. Such routes include transdermal, intraarticular, oral, intranasal and intraocular.
2. Opioids and Opioid Antagonists
Morphine is a classic example of an opiate analgesic that acts on the CNS receptors for the naturally occurring opioid peptides, the enkephalins and endorphins, mimicking their action. It is a powerful addictive drug used for the relief of moderate to severe pain associated with conditions such as heart attack, cancer, colic due to kidney or gall stones, following surgery and for severe burns etc. It has a short biological half-life and is normally delivered orally or by injection. Related opioid analgesic or antagonists include hydromorphone, oxymorphone, levorphanol, levallorphan, codeine, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol and nalbufine.
Morphine has the structure:
Modification of the hydroxyl groups at position 3 or 6 with lipophilic groups change the rate of absorption and distribut

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