Hyperforin derivatives, use thereof and formulations...

Details Hyperforin derivatives, use thereof and formulations... Hyperforin derivatives, use thereof and formulations...

2000-12-07

2003-12-02

Tate, Christopher R. (Department: 1654)

Drug, bio-affecting and body treating compositions

Plant material or plant extract of undetermined constitution...

Containing or obtained from hypericum

C514S732000

Reexamination Certificate

active

06656510

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel hyperforin derivatives, the use of such derivatives for the treatment of depression and anxiety, and to formulations containing them.
BACKGROUND OF THE INVENTION
Flowering tops of
Hypericum perforatum
contain a number of classes of structurally different substances that act directly or indirectly on the central nervous system. In particular, these compounds include hypericin, hyperforin, and dimeric flavones that exert antidepressive and anxiolycic activities on animals and humans. The mechanisms of action of these compounds are different and include anti-MAO action, action on serotonin release, and benzodiazepine-like activity. Hyperforin is one of the main components of the lipophilic fraction of
Hypericum perforatum
flowering tops and has recently been the subject of numerous studies that establish its important role as an antidepressant. Applicant has discovered that this molecule has serotoninmimetic activity.
Hyperforin is not very stable to typical extraction and storage conditions. WO 97/13489 to Schwabe shows that the hyperforin content of a water-alcohol extract of St. Johns wort falls almost to zero after only a few weeks. WO 97/13489 further recites that in order to obtain stable extracts with a constant hyperforin content, extraction, purification, and storage should be carried out in the presence of antioxidants such as vitamin C and the esters thereof, sulfated amino acids, and the like. The high instability of hyperforin makes the preparation of hyperforin formulations rather difficult.
SUMMARY OF THE INVENTION
The invention relates to a compound having the formula:
wherein R is a saturated or unsaturated, straight or branched, C
1
-C
22
acyl group, optionally having one or more substituents, which can be the same or different, selected from a group consisting of halogen atoms, nitro, amino, C
1
-C
6
-alkylamino, di-C
1
-C
6
-alkylamino, and C
1
-C
6
-acylamino groups; a cycloaliphatic or aromatic acyl residue wherein the aromatic moiety optionally has one or more substituents, which can be the same or different, selected from the group consisting of halogen atoms, hydroxy, methoxy, and amino groups; or a glycidic residue wherein one or more hydroxy groups are optionally alkylated or acylated. The invention also relates to an extract of
Hypericum perforatum
containing this compound.
The invention further relates to a process for preparing extracts including the compound of formula I. The method involves extracting
Hypericum perforatum
flowering tops with supercritical CO
2
to obtain a lipophilic extract; dissolving the lipophilic extract in aqueous methanol or acetonitrile to form a hydrophilic phase; extracting the hydrophilic phase with aliphatic hydrocarbons to provide a first aliphatic hydrocarbon phase; diluting the hydrophilic phase with water and counter-extracting the phase with aliphatic hydrocarbons to provide a second aliphatic hydrocarbon phase; combining the first and second aliphatic hydrocarbon phases; concentrating the combined first and second aliphatic hydrocarbon phases; treating the concentrate with a reactive derivative of a RCOOH acid or of an ROH sugar, wherein R is a saturated or unsaturated, straight or branched, C
1
-C
22
acyl group, optionally having one or more substituents, which can be the same or different, selected from the group consisting of halogen atoms, nitro, amino, C
1
-C
6
-alkylamino, di-C
1
-C
6
-alkylamino, and C
1
-C
6
-acylamino groups; a cycloaliphatic or aromatic acyl residue in which the aromatic moiety optionally has one or more substituents, which can be the same or different, selected from the group consisting of halogen atoms, hydroxy, methoxy, and amino groups; or a glycidic residue wherein one or more hydroxy groups are optionally alkylated or acylated.
The invention also relates to a pharmaceutical composition including the compound of formula I and a pharmaceutically acceptable carrier or extract. This pharmaceutical composition is further formulated as a soft-gelatin capsule, hard-gelatin capsule, tablet, or suppository. In a preferred embodiment, the composition includes from 5 to 50 mg of the compound. The pharmaceutical composition can also be formulated as a controlled release dosage form. In a preferred embodiment, the composition includes up to 200 mg of the compound.
The invention also relates to a method of treating depression in an animal including administering to an animal the compound of formula I and extracts thereof.
DETAILED DESCRIPTION OF THE INVENTION
New hyperforin derivatives have been discovered that are stable and more active as antidepressants. The derivatives of the invention have the following formula:
wherein R is:
a saturated or unsaturated, straight or branched, C
1
-C
22
acyl group, optionally having one or more substituents, which can be the same or different, selected from halogen atoms, nitro, amino, C
1
-C
6
-alkylamino, di-C
1
-C
6
-alkylamino, C
1
-C
6
-acylamino groups;
a cycloaliphatic or aromatic acyl residue in which the aromatic moiety has optionally one or more substituents, which can be the same or different, selected from halogen atoms, hydroxy, methoxy, amino groups;
a glycidic residue in which one or more hydroxy groups are optionally alkylated or acylated.
Preferably the “aromatic acyl residue” is a benzoyl or cinnamyl residue having one or more amino or alkoxy groups.
Preferably the “glycidic residue” is a residue of one sugar bound by an ether bond to the hydroxy group at the 1-position of the pyranosyl or furanosyl ring, with the other hydroxy groups of the sugar optionally methylated or acetylated.
Preferably R is acetyl, monochloroacetyl, butyryl, &ggr;-aminobutyryl, p-aminobenzyl, trimethoxybenxyl, trimethoxycinnamyl, &bgr;-glucosyl, or &bgr;-galactosyl.
The hyperforin derivatives of the invention can be prepared with conventional methods, well know to those of ordinary skill in the art, for acylation or glycosylation of hydroxy groups. For example, hyperforin, either as substantially pure or as an extract enriched in hyperforin, can be subjected to a reaction with acid chlorides or anhydrides of RCOOH acids ® as defined above) in suitable solvents, such as pyridine.
Glycosylations can be carried out using a suitably protected reactive derivative of the desired sugar (ROH), for example &agr;-D-glucopyranosyl bromide tetraacetate.
A particularly convenient aspect of the invention is that the compounds of formula I can be prepared by extracting
Hypericum perforatum
flowering tops with carbon dioxide under supercritical conditions, subsequently partitioning the extract between solvents, and derivatizing hyperforin in the resulting extract.
Leaves and flowering tops of St. Johns wort, separately or in mixtures, preferably as natural mixtures, are extracted with carbon dioxide in supercritical conditions under pressures of 180 to 260 bars, preferably about 240 bars, and at temperatures of 35° C. to 50° C., preferably 40° C. A lipophilic extract is obtained containing about 50% hyperforin and considerable amounts of xanthones, waxes, fatty acids, and triglycerides. The hyperforin percentage is subsequently increased by dissolving the resulting extract in methanol or in partially aqueous acetonitrile and then extracting the solution with n-hexane or aliphatic hydrocarbons. The hydrocarbon phase also contains undesirable substances which are removed. The hydrophilic phase is then diluted with about equal volumes of water and aliphatic hydrocarbons and the hydrocarbon layers are combined. The extract of St. Johns wort obtained by concentration of the hydrocarbon phase can be used for the preparation of the derivatives as described above.
The derivatives of the invention exert no activity in vitro on receptors, but are particularly active in vivo, exerting strong antidepressive activity that is related to the dosage. In an in vivo test in mice and rats, the compounds of the invention showed a higher activity than hyperforin and Hypericum ethanol or methanol extracts. The escape deficit developm

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