Androgen derivatives and uses thereof

Details Androgen derivatives and uses thereof Androgen derivatives and uses thereof

2000-05-04

2003-10-07

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S005000, C536S006000

Reexamination Certificate

active

06630453

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to androgen derivatives and their use in therapy.
2. Related Art
Testosterone, an anabolic androgenic C19 steroid with a hydroxy group in position 17, is the principal male sex hormone. It is either synthesised from cholesterol and secreted by the Leydig cells in the testes or formed in the adrenal cortex [Ganong, Chapter 23 in
Review of Medical Physiology
, (1979), pp. 336-339]. Testosterone is found in androgen dependent target tissues, such as the testes, kidneys, skin, liver and prostate, where it is converted to 5&agr;-dihydrotestosterone (DHT) by 5&agr;-reductase. DHT is required for male sexual differentiation. Testosterone is also found in the brain where it is converted to oestradiol by aromatase. This conversion permits mediation of androgenic effects which include gonadotropin secretion regulation, sexual function and protein synthesis [Handelsman, “Testosterone and Other Androgens: Physiology, Pharmacology, and Therapeutic Use,” in
Endocrinology—Volume
3, Ed's DeGroot et al., (1995), pp. 2351-2361].
Testosterone is also found in skeletal muscle. However, testosterone is not converted to DHT in skeletal muscle tissue, due to low 5&agr;-reductase activity (Handelsman, supra). According to Catlin, anabolic androgenic steroids, such as testosterone, increase the width and cross-sectional area of muscle fibres by increasing the myofilament and myofibre number [Catlin, “Anabolic Steroids,” in
Endocrinology—Volume
3, Ed's DeGroot el al. (1995), pp. 2362-2376]. In hypogonadal men, this results in an increase in lean body mass and body weight, and a decrease in body fat [Handelsman, “Testosterone and Other Androgens: Physiology, Pharmacology, and Therapeutic Use,” in
Endocrinology—Volume
3, Ed's DeGroot et al. (1995), pp. 2351-2361; Catlin, “Anabolic Steroids,” in
Endocrinology—Volume
3, Ed's DeGroot et al. (1995), pp. 2362-2376].
Testosterone and related synthetic androgens are often used in androgen replacement therapy to obtain pharmacological androgenic effects to treat conditions such as hypogonadism. Hypogonadism may be caused by a testosterone deficiency, resulting in manifestations of androgen deficiency, such as ambiguous genitalia, sexual dysfunction, osteoporosis, flushing, delayed puberty, microphallus, anaemia, incidental biochemical diagnosis or excessive fatigability [Handelsman, “Testosterone and Other Androgens: Physiology, Pharmacology, and Therapeutic Use,” in
Endocrinology—Volume
3, Ed's DeGroot et al. (1995), pp. 2351-2361]. Androgen replacement therapy has also been used to treat muscular diseases. However, such treatment generally involves administering orally active 17&agr;-alkylated androgens which are hepatotoxic [Handelsman, “Testosterone and Other Androgens: Physiology, Pharmacology, and Therapeutic Use,” in
Endocrinology—Volume
3, Ed's DeGroot et al. (1995), pp. 2351-2361].
In hypogonadism treatment, androgen replacement therapy often consists of administering testosterone compounds to an individual to maintain testosterone levels for a prolonged period. Testosterone is ineffective, when orally administered, due to poor intestinal absorption and rapid hepatic metabolism [Daggett et al.,
Hormone Res
. 9:121-129 (1978)]. Therefore, the effects of testosterone must be obtained by alternative means including administering sublingual methyl testosterone, injecting testosterone or testosterone esters, implanting testosterone, administering oral testosterone derivatives, e.g., fluoxymesterone, or applying testosterone by transdermal means [Bals-Pratsch et al.,
Acta Endocrinologica
(
Copenh
), 118:7-13 (1988)]. The latter method requires large patches which can be irritating or uncomfortable when applied to the scrotum. In addition, patch application can be inconvenient and is only effective when detailed instructions are followed.
Oral testosterone derivatives include 17&bgr;-esters, 7&agr;-methyl, 17&agr;-alkyl or methyl, 19-normethyl and D-homoandrogens [Handelsman, “Testosterone and Other Androgens: Physiology, Pharmacology, and Therapeutic Use,” in
Endocrinology—Volume
3, Ed's DeGroot el al. (1995), pp. 2351-2361]. Other known testosterone derivatives include testosterone substituted at the C1 position with methyl, e.g., methenolone and mesterolone. However, these compounds have reduced oral potency. Compounds with substitutions in, and additions to, the A ring, e.g., oxandrolone and stanozolol, are also known (Catlin, supra).
Testosterone has also been used in combination with a progestogen to achieve reversible male contraception [Wu et al.,
Journal of Clinical Endocrinology and Metabolism
84(1): 112-122 (January 1999)].
U.S. Pat. No. 5,612,317 discloses methods of treating and preventing osteoporosis and alleviating the symptoms of menopause by administering an oestrogen glycoside or oestrogen orthoester glycoside. The compounds have the formula (I):
wherein R
1
and R
2
are independently hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue, or R
1
or R
2
is an orthoester glycoside moiety of the Formula (II):
wherein A represents a glycofuranosyl or glycopyranosyl ring;
R
3
is hydrogen; lower C
1-4
alkyl; C
7-10
aralkyl; phenyl or phenyl substituted by chloro, fluoro, bromo, iodo, lower C
1-4
alkyl or lower C
1-4
alkoxy; or naphthyl; and
R
4
is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue;
with the further proviso that at least one of R
1
and R
2
is either a glycosidic residue or an orthoester glycoside moiety.
Hirotani and Furuya disclose the biotransformation by cultured tobacco cells of the C-19 steroid testosterone into a variety of steroid glucosides, one of which is testosterone-17-glucoside [Hirotani and Furuya,
Phytochemistry
13: 2135-2142 (1974)].
Kocovský et al. disclose the synthesis of a variety of steroid glucosides including testosterone-17-glucoside and testosterone-17-glucoside tetraacetate [Kocovský et al.,
Coll. Czech. Chem. Commun
. 38:3273-3278 (1978)].
Becker and Galili disclose the synthesis of testosterone-17-glucoside [Becker and Galili,
Tetrahedron Lett
. 33:4775-4778 (1992)].
Vojtí{haeck over (s)}ková et al. disclose a study on the biological activity of testosterone-17-glucoside in mice [Vojtí{haeck over (s)}ková et al.,
Int. J. Immunopharmac
. 4: 469-474 (1982)]. This glucoside showed very little activity in vivo, and certainly less than testosterone administered by the same route.
It has now, surprisingly, been found that androgen glycosides taken orally are less susceptible to hepatic degradation than the corresponding unglycosylated androgen and are only substantially de-glycosylated after the first passage through the liver, thereby resulting in higher circulatory levels of the androgen. These compounds also appear to be more susceptible to gastric uptake.
SUMMARY OF THE INVENTION
The invention relates to an androgen glycoside that is not testosterone-17-&bgr;-1′-&bgr;′-D-glucopyranose.
The invention further relates to a compound having the Formula (III):
wherein the dotted line represents a single or double bond;
the rings P and Q are, independently, saturated or partially unsaturated;
R is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue, or R is an orthoester glycoside moiety of the Formula (IV):
wherein the semi-dotted ring indicated at “C” is a glycofuranosyl or glycopyranosyl ring;
R
8
is hydrogen; C
1-4
alkyl; C
7-10
aralkyl; phenyl; phenyl substituted by chloro, fluoro, bromo, iodo, C
1-4
alkyl or C
1-4
alkoxy; or is naphthyl;
R
9
is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycoside units;
R
1
is hydrogen, C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl, C
1-4
alkanoyl or R
1
and R, together wi

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