Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-11
2002-09-24
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S027000
Reexamination Certificate
active
06455580
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to treatment of disease of viral origin in warm-blooded vertebrates. More particularly, this invention is directed to the use of secoiridoid compounds naturally occurring in plants of the family Oleaceae and derivatives thereof.
BACKGROUND AND SUMMARY OF THE INVENTION
The olive tree and other members of the Family Oleaceae have been documented as a source of medicinal substances since biblical times. Needless to say, many researchers have studied the cocktail of phytogenic substances produced by the olive and other members of the Family Oleaceae. One compound that has received attention from the research community is the secoiridoid glucoside oleuropein, a compound of the formula
wherein R is glycosyl and R
1
is 2-(3,4-dihydroxyphenyl) ethyl. Related secoiridoids wherein R
1
is H, CH
3
or 2-(4-hydroxyphenyl ethyl) are also known to be endogenous to many plant species of the family Oleaceae, although in lesser concentrations and in fewer identified species than the ubiquitous oleuropein.
Animal studies have revealed that oleuropein itself or as a component of extracts of plant tissues containing that compound exhibit both hypoglycemic and cardiovascular effects. It is also known that oleuropein can be acid hydrolyzed to produce (−)-elenolic acid, a compound which has been reported to have antiviral properties in vitro, but little, if any, activity in vivo.
The present invention is based on the discovery that secoiridoid glucosides of the formula
wherein R is glycosyl and R
1
is hydrogen or an ester-forming group are metabolized in vivo to the dextrorotatory form of elenolic acid [(+)-elenolic acid], a compound of the formula
wherein R
1
is hydrogen, a compound which is believed to be more available in vivo than the corresponding diasteromer(−)-elenolic acid of the formula
The enhanced in vivo efficacy of the oleuropein metabolite, (+)-elenolic acid relative to the corresponding levorotatory compound is thought to be due, at least in part, to its reduced affinity for serum proteins and thus its greater availability for uptake by virus infected tissues. Antivirally effective blood levels of (+)-elenolic acid can also be achieved by administration of (+)-elenolic acid and its esters of the formula
wherein R
1
is hydrogen or a pharmaceutically acceptable ester-forming group and salts thereof, which can be prepared from secoiridoid glucosides naturally occurring in plant material of the family Oleaceae via extraction and controlled enzyme (glucosidase) hydrolysis and/or deesterification/transesterification reactions.
Thus, it is one object of the present invention to provide a method of treatment of disease of viral origin in warm-blooded vertebrates by administering antiviral compositions containing secoiridoid glucosides native to the plant family Oleaceae and derivatives thereof.
Another object of the invention is to provide oral dosage forms of secoiridoid glucosides of
Olea europaea
and derivatives thereof.
In another more particular aspect of this invention plant material of the family Oleaceae and extracts thereof containing naturally occurring oleuropein glucosides and enzyme hydrolysates thereof are administered in treatment of diseases of viral origin in warm-blooded vertebrates suffering from such diseases.
One further object of this invention is a method for establishing antivirally effective blood levels of (+)-elenolic acid by the administration of oleuropein glucosides native to the family Oleaceae or their derivatives via transesterification, diesterification and/or glucolysis.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a method of treatment of disease of viral origin in warm-blooded vertebrates and to pharmaceutical formulations for use in such treatment methods. The method comprises the step of administering to a vertebrate suffering from a disease of viral origin an antivirally effective amount of an antiviral composition comprising a compound of the formula
and a pharmaceutically acceptable carrier therefor. In the above formula, the group R is glucosyl and R
1
is hydrogen or a pharmaceutically acceptable ester-forming group. When R
1
is hydrogen, the acid compound represented can be utilized in the form of one of its pharmaceutically acceptable salts.
There are many diseases of viral etiology that afflict man and animal. In man, diseases such as hepatitis, mononucleosis, shingles, herpes, influenza, the common cold and even certain types of leukemia are known to be of viral etiology. Viral infections are also common in many animal species, both in meat producing and in companion animals. Rotovirus infections plague swine. Cattle develop bovine rhinovirus infections (shipping fever) when subjected to conditions of stress. Canine parvovirus and feline leukemia virus are common viral infections in those companion animals species. Such diseases of viral origin can be treated with resultant reduction in clinical symptomology by therapeutic administration of antiviral compositions in accordance with this invention.
The antiviral compositions administered in accordance with this invention comprise a compound of Formula I or II above in combination with a pharmaceutically acceptable carrier. The compounds of Formula I wherein R
1
is 2-(4-hydroxyphenyl)ethyl or 2-(3,4-dihydroxyphenyl)ethyl are naturally occurring compounds in many plants of the Family Oleaceae, including members of the genus Fraxinus, Syringa and the genus Ligustrum. Preferred plant sources of the naturally occurring secoiridoids of Formula I wherein R
1
is 2-(4-hydroxyphenyl)ethyl and 2-(3,4-dihydroxyphenyl)ethyl are varieties of
Olea europaea
(the olive). Preferred varieties of
Olea europaea
as a source of secoiridoid glycosides for use in accordance with this invention are the varieties Manzanillo and Mission.
The most prevalent of the secoiridoid compounds in such varieties is the compound of Formula I wherein R
1
is 2-(3,4-dihydroxyphenyl)ethyl and R is glucosyl, a compound given the common name oleuropein. That compound can be readily isolated from plant material, preferably ground leaves of the olive by aqueous or aqueous-alcoholic extraction at room temperature or above, preferably at elevated temperature of about 40 to about 100° C.
Oleuropein can then be purified, for example, by chromatographic separation procedures. That compound can then be used to formulate antiviral compositions in accordance with this invention or to prepare other antivirally effective compounds represented by Formulas I or II. Thus, for example, oleuropein can be subjected, to base catalyzed transesterification wherein the R
1
group 2-(3,4-dihydroxyphenyl)ethyl is exchanged with another pharmaceutically acceptable ester-forming group. The term “pharmaceutically acceptable ester-forming group” as used in defining the present invention, refers to those ester-forming groups which when cleaved via esterase reactions in vivo produce substantially non-toxic, physiologically compatible alcohols. Suitable pharmaceutically acceptable ester-forming groups include C
1
-C
8
lower alkyl, and substituted C
1
-C
8
alkyl, benzyl, substituted benzyl wherein the substituents are halo, C
1
-C
4
alkoxy, C
1
-C
4
acyloxy, and the like. The compound of Formula I wherein R
1
is hydrogen can be produced by esterase-mediated deesterification of oleuropein, typically in an aqueous medium at a pH between about 6 and about 8.5.
The compounds of Formula II are prepared from the corresponding compounds of Formula I by treatment with glucosidase, preferably that from the olive at a pH of about 4 to about 5. The compound of Formula II wherein R
1
is hydrogen is (+)-elenolic acid.
The compounds of Formula I or II wherein R
1
is hydrogen represent carboxylic acids and such acids can be used in accordance with this invention in the acid form or in the form of their pharmaceutically acceptable salts formed with organic bases or inorganic bases, such as ammonium, alkali or alkaline earth metal hydr
Barnes & Thornburg
F&S Group, Inc.
Travers Russell
LandOfFree
Method and composition for antiviral therapy does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method and composition for antiviral therapy, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method and composition for antiviral therapy will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2834997