Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2002-01-16
2004-05-25
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S182000, C552S633000
Reexamination Certificate
active
06740646
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 or prohormones of androgenic steroids and related methods.
2. Description of the Related Art
The importance of having sufficient concentrations of androgenic steroids in the body is well known. The advantages of such steroids can include such things as increased physical performance, improved body composition or increased density, and increased sexual drive or performance, depending upon the specific steroid, organism, etc. It is equally well known that under many common circumstances, deficiencies of these androgenic steroids arise. In humans, for example, as one ages, the normal concentrations of these steroids tend to decrease. Men over the age of about thirty-five typically suffer a reduction in the blood serum concentration of free testosterone. These changes typically result in a reduced general athletic performance and longer time requirements for restoration after extensive exercise, as well as reduced physical and psychological resistance to stress.
A known approach to addressing such steroid concentration deficiencies is to introduce the deficient steroid into the body. In U.S. Pat. No. 5,578,588, for example, methods are disclosed for delivering testosterone supplements including peroral administration or intramuscular injection of testosterone.
This approach, however, suffers from a number of disadvantages. Introduction of such steroid supplements has been associated with undesirable effects such as poor control over blood concentrations and loss of the steroid due to a “first pass effect,” wherein the steroid is metabolized by the liver prior to reaching general circulation. These losses dramatically reduce the available steroid and, consequently, much higher doses of the steroid supplement generally must be administered to achieve the desired effects. The higher doses sometimes result in an undesirable and unpredictable rise in overall steroid concentration, which, for example, in the case of testosterone, can result in physiological and psychological problems.
Another approach to addressing steroid concentration deficiencies is to introduce a prodrug of the steroid into the body. An example of a prodrug is a prohormone. A prohormone is a compound that itself has no anabolic activity but, when administered in the body, is metabolized or converted into a natural or desired hormone. Such prohormones become substrates for in vivo bioconversion into the parent compounds, i.e., the corresponding natural or desired hormones. U.S. Pat. No. 5,053,403, for example, discloses that specific prohormones including androstenedione, progesterone, and 17&agr;-&bgr; derivatives or analogues can be administered to humans for the purpose of increasing blood concentration of testosterone, with fewer undesirable effects. Long term use of these prohormones, however, is also associated with side effects, such as gynecomastia. A pernasal dose of 3.5 mg to 15 mg of these prohormones is reported to increase the blood concentration of testosterone by 34% to 97%. Similarly, U.S. Pat. No. 5,880,117 discloses the use of 4-androstenediol as a peroral testosterone supplement. Androstenedione is a direct precursor of testosterone and estrogen in target tissues having appropriate receptors and enzymes. According to U.S. Pat. No. 6,117,429, androstenediols are precursors for testosterone after oral administration in adults. 19-norandrostenedione is a precursor for 19-nortestosterone, which has a similar anabolic activity in comparison to testosterone.
The general approach of using prodrugs or prohormones to achieve supplementation of androgenic steroid concentrations in vivo also has been limited, however, in that the effectiveness of such compounds has tended to be low. In some instances, their conversion into the desired steroid is limited, for example, because they are removed from the system through the first pass effect. They also can be converted into undesirable products, for example, as in the case wherein 4-androstenedione is converted into estrogen. 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 results. 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, sublingual or pernasal 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 a parent androgen.
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 androgen with while being amenable to convenient administration, such as by oral, sublingual or pernasal 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 is provided for increasing the concentration of a parent androgen in a subject in vivo, wherein the parent androgen has a skeletal structure including a 1 position and a 17 position and the parent androgen further has a 17&bgr;-hydroxy group comprising a 17&bgr;-hydroxy oxygen appended to the 17 position and a 17&bgr;-hydroxy hydrogen appended to the 17&bgr;-hydroxy oxygen.
The compound according to this aspect of the invention comprises a substrate having the skeletal structure of the parent androgen comprising a 1 position and a 17 position corresponding to the 1 and 17 positions respectively of the parent androgen. The substrate further comprises a carbon—carbon double bond at the 1 position. The compound also comprises a promoiety appended to the 17 position of the substrate as a substitute for the 17&bgr;-hydroxy hydrogen of the parent androgen. The promoiety comprises an alkylcarbonate ester.
The substrate has the skeletal structure of the parent androgen, preferably wherein the parent androgen is selected from the group consisting of 5&agr;-androst-1-ene-3&agr;, 17&bgr;-diol, 5&agr;-androst-1-ene-3&bgr;, 17&bgr;-diol, and mixtures thereof. The substrate also may have the skeletal structure of the parent androgen wherein the parent androgen is selected from the group consisting of 5&agr;-estr-1-ene-3&agr;, 17&bgr;-diol, 5&agr;-estr-1-ene-3&bgr;, 17&bgr;-diol, and mixtures thereof. In addition, the parent androgen to which the substrate corresponds may comprise 17&bgr;-hydroxy-5&agr;-androst-1-ene-3-one. The substrate still further may have the skeletal structure of the parent androgen wherein the parent androgen is selected from the group consisting of 17&bgr;-hydroxyandrost-1,4-diene-3-one, 17&bgr;-hydroxyestr-1,4-diene-3-one, 17&bgr;-hydroxy-5&agr;-estr-1-ene-3-one, and mixtures thereof.
The alkylcarbonate ester optionally but preferably has an alkyl chain length of less than 12, and more preferably of less than 11. The alkylcarbonate ester may be 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 carbona
Badio Barbara P.
Biotest Laboratories, LLC
Sullivan Law Group
LandOfFree
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