Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-12
2004-11-16
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S457000, C549S402000, C549S403000
Reexamination Certificate
active
06818668
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention pertains to the field of biochemistry and more specifically to the field of prodrugs of metabolic agents and related methods.
2. Description of the Related Art
The use of isoflavones as metabolic agents is described in U.S. Pat. No. 4,163,746 to Feuer, assigned to Chinoin Gyogyszer es Vegyeszeti Termekek Gyara Rt. of Hungary (“the Feuer '746 patent”). The Feuer '746 patent identifies a class of isoflavones characterized as possessing a methyl group at the 5-carbon position and a hydroxyl or ether group at the 7 carbon position. The Feuer '746 patent lists 5-methyl-7-methoxy-isoflavone, 5-methyl-7-ethoxy-isoflavone, 5-methyl-7-(2-hydroxy-ethoxy)-isoflavone, and 5-methyl-7-isopropoxy-isoflavone as preferred isoflavones.
The Feuer '746 patent purports that its class of isoflavones were shown to have utility in promoting anabolic activity and increasing calcium, phosphorous, potassium, and nitrogen retention to a significant degree. The list of preferred isoflavones mentioned above also is purported to produce a significant weight gain increase in domestic animals, with the weight surplus consisting of meat, rather than fat. According to the Feuer '746 patent, perhaps the most significant advantage of its class of isoflavones over conventional anabolic agents was that its isoflavones did not produce androgenic or liver damaging side effects. Due to its anabolic properties, the isoflavones of the Feuer '746 patent are described as having utility in the treatment of diseases, and particular utility in the treatment of osteoporosis of gerontological and immobilation origin.
Without necessarily wishing to be bound by any theory, it is believed that the isoflavones described in the Feurer '746 patent, such as 5-methyl- 7-methoxy-isoflavone, are prodrugs, that is, a compound that itself has no anabolic activity but, when administered in the body, is metabolized or converted into a natural or desired form, 7-hydroxy-5-methyl-isoflavone, which promotes anabolic activity. Thus, such prodrugs, i.e., 5-methyl-7-methoxy-isoflavone, become substrates for in vivo bioconversion into the desired parent compounds. (Incidentally, if 7-hydrox-5-methyl-isoflavone were administered directly, i.e., not in a prodrug state, the liver would likely metabolize substantially all of the 7-hydroxy-5-methyl-isoflavone during the first pass.)
Based on findings of the Feurer '746 patent and other reported research, the compound 5-methyl-7-methoxy-isoflavone is commercially sold as a nutritional supplement and advertised as an anabolic agent for promoting muscle mass gains and body fat composition losses, while not causing adverse side effects associated with the use of steroids.
However, the effectiveness of the prodrug 5-methyl-7-methoxy isoflavone has been limited due to difficulties that the human body encounters in converting the prodrug to its parent isoflavone in vivo. In some instances, its conversion into the desired parent compound, 7-hydroxy-5-methyl-isoflavone, is limited, for example, because it is removed from the system through the “first pass effect,” wherein the compound is metabolized by the liver prior to reaching general circulation. A large proportion of the prodrug also either does not undergo conversion or converts into undesirable products. It is estimated that approximately 50% of the prodrug 5-methyl-7-methoxy isoflavone administered to a human is converted in vivo to 7-hydroxy-5-methyl-isoflavone. Even where the desired bioconversion occurs, the rate of conversion can be sufficiently low that undesirably large quantities of the prodrug must be taken to achieve desired effects. This itself can have undesirable side effects.
It is advantageous in many instances to have a prodrug that may be administered in a convenient form, such as by oral, or sublingual administration. Many prodrugs have not been amenable to such administration, however, because they tend to be broken down prior to absorption in vivo when administered in this fashion.
OBJECTS OF THE INVENTION
Accordingly, an object of the present invention is to provide compositions and methods that can be used to increase the in vivo concentration and bioavailability of the parent compound, 5-alkyl-7-hydroxy-isoflavone.
Another object of the invention according to certain aspects is to provide compounds and methods that can be used to increase the in vivo concentration and bioavailability of a parent 5-alkyl-7-hydroxy-isoflavone while being amenable to convenient administration, such as by oral, or sublingual administration.
Additional objects and advantages of the invention will be set forth in the description that follows, and in part will be apparent from the description, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and obtained by means of the instrumentalities and combinations pointed out in the appended claims.
SUMMARY OF THE INVENTION
To achieve the foregoing objects, and in accordance with the purposes of the invention as embodied and broadly described in this document, a compound comprising an alkylcarbonate ester is provided. The compound represented by the formula I
wherein R
1
consists of a member selected from the group consisting of a straight-chain, branched, and cyclic alkyl; R
2
consists of a member selected from the group consisting of a straight-chain, branched, and cyclic alkyl; R
3
and R
4
are the same or different, and selected from the group consisting of hydrogen, alkyl, hydroxy, and alkyoxy; and R
5
consists of a member selected from the group consisting of hydrogen and an alkyl.
The alkylcarbonate ester optionally but preferably has an alkyl chain length of not more than 12, and more preferably of less than 11. The alkylcarbonate ester may consists of a member selected from the group consisting of methyl carbonate, ethyl carbonate, propyl carbonate, isopropyl carbonate, butyl carbonate, isobutyl carbonate, t-butyl carbonate, valeryl carbonate, hexyl carbonate, heptyl carbonate, octyl carbonate, nonyl carbonate, decyl carbonate, undecyl carbonate, dodecyl carbonate, cyclopentyl carbonate, cyclopentylmethyl carbonate, cyclopentylpropyl carbonate, cyclohexylmethyl carbonate, cyclohexylpropyl carbonate, and mixtures thereof. Alkyl carbonate esters having lower carbon chain lengths generally are preferred, although not universally so. The ethyl carbonate is a preferred form of the alkylcarbonate in the molecule. The compound itself according to this aspect of the invention may assume a number of specific forms. It may, for example, comprise 5-methyl-7-ethylcarbonate-isoflavone. It also may take the form of mixtures or combinations of compounds.
In accordance with a preferred variation of the first aspect of the invention, the compound has the following formula II
wherein R
1
consists of a member selected from the group consisting of a straight-chain, branched, and cyclic alkyl; and R
2
consists of a member selected from the group consisting of a straight-chain, branched, and cyclic alkyl.
In accordance with a second aspect of the invention, a compound is provided for increasing the concentration of a parent isoflavone in a subject in vivo. The parent isoflavone has a skeletal structure including a 5 position and a 7 position and the parent isoflavone further has a 5 alkyl group, and a 7-hydroxy group comprising a 7-hydroxy oxygen appended to the 7 position and a 7-hydroxy hydrogen appended to the 7-hydroxy oxygen.
The compound of the second aspect of the invention comprises a substrate having the skeletal structure of the parent isoflavone. The substrate comprises a 5 position and a 7 position corresponding to the 5 and 7 positions respectively of the parent isoflavone. A straight-chain, branched, or cyclic alkyl group is appended to the 5 position. A promoiety is appended to the 7-hydroxy oxygen of the substrate as a substitute for the 7-hydroxy hydrogen of the parent isoflavone, the promoiety and the 7-hydroxy oxygen establishin
Biotest Laboratories, LLC
Covington Raymond
Seaman D. Margaret
Sullivan Law Group
LandOfFree
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