Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-03-10
2003-04-01
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C540S041000, C540S044000
Reexamination Certificate
active
06541463
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to inhibitors of enzymes involved in the biosynthesis of sex steroids from natural precursors and to their use in the treatment of sex steroid dependent diseases. In particular, inhibitors are disclosed which suppress the activity of type 3 and type 5 17&bgr;-hydroxysteroid dehydrogenase, thus diminishing the production of androgens catalyzed by these two enzymes. Pharmaceutical use of the inhibitors may reduce the natural production of androgens such as testosterone and dihydrotestosterone, and thereby beneficially treat diseases whose onset or progress is aided by androgenic activity. Because androgens formed by reactions catalyzed by type 3 or type 5 enzyme are precursors to estrogens, the invention also has applicability to diseases whose onset or progress is aided by estrogenic activity.
BACKGROUND OF THE RELATED ART
Many androgen-sensitive diseases, i.e. diseases whose onset or progress is aided by androgenic activity, are known. They include but are not limited to prostate cancer, benign prostatic hyperplasia, acne, seborrhea, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia, and polycystic ovarian syndrome. Estrogen sensitive diseases, i.e. diseases whose onset or progress is aided by estrogenic activity are also known. They include but are not limited to breast cancer, endometriosis, leiomyoma, and precocious puberty.
Precocious puberty is usually associated with an excess of androgen secretion, usually of adrenal origin. The current treatments include blockade of adrenal secretion by glucocorticoids with its associated side effects. Blockade of type 5 17&bgr;-HSD would be an advantage, thus desirably reducing the dose or avoiding the use of glucocorticoids. Another treatment is the use of LHRH agonists to cause medical castration. A better controlled inhibition of androgen formation could be achieved with type 5 and 3 17&bgr;-HSD inhibitors.
Polycystic ovarian syndrome is associated with an excess of androgen secretion by the ovaries. LHRH agonists are used among other, as treatment, to cause medical castration. The use of an inhibitor of 17&bgr;-HSD would be advantageous.
Estrogen sensitive diseases may vary in their responses to androgens. They may, for example, respond favorably, unfavorably or not at all to androgens. Likewise, androgen-sensitive diseases may respond differently to estrogens. Thus, the treatment of sex steroid sensitive diseases may involve increasing or decreasing androgenic activity depending on whether the disease in question responds favorably or unfavorably to androgenic activity. Treatment may also involve increasing or decreasing estrogenic activity depending on whether the disease in question responds favorably or unfavorably to estrogenic activity. Breast cancer, for example, is known to respond favorably to androgenic activity and negatively to estrogenic activity. Benign prostatic hyperplasia is believed to respond negatively to both androgenic and estrogenic activity.
Androgenic and estrogenic activity may be suppressed by administering androgen receptor antagonists (“antiandrogens”) or estrogen receptor antagonists (“antiestrogens”), respectively. See e.g. WO 94/26767 and WO 96/26201. Androgenic and estrogenic activity may also be reduced by suppressing androgen or estrogen biosynthesis using inhibitors of enzymes that catalyze one or more steps of such biosynthesis or by suppressing ovarian or testicular secretions by known methods. See e.g. WO 90/10462, WO 91/00731, WO 91/00733, and WO 86/01105. Type 5 17&bgr;-hydroxysteroid dehydrogenase is described in WO 97/11162.
Effective inhibitors of type 5 17&bgr;-hydroxysteroid dehydrogenase enzyme are provided by the present invention. The prior art is not believed to have provided compounds sufficiently effective at simultaneously (1) inhibiting type 5 or type 3 17&bgr;-hydroxysteroid dehydrogenase while (2) desirably failing to substantially inhibit other 17&bgr;-hydroxysteroid dehydrogenases or other catalysts of sex steroid degradation. Medroxyprogesterone acetate, megestrol acetate, and chlormadinone acetate which the prior art as used as pharmaceutical agents for other purposes are not believed to have been disclosed as inhibitors of type 5 17&bgr;-hydroxysteroid dehydrogenase, although applicants' research has now shown them to inhibit that type 5 enzyme.
SUMMARY OF THE INVENTION
It is accordingly an object of the present invention to more selectively and effectively inhibit type 3 and/or type 5 17&bgr;-hydroxysteroid dehydrogenase while preferably avoiding inhibition of other 17&bgr;-hydroxysteroid dehydrogenases, type 1 or 2 3&agr;-hydroxysteroid dehydrogenases, or other androgen degradation enzymes.
It is another object to provide novel inhibitors of types 3 and 5 17&bgr;-hydroxysteroid dehydrogenase and pharmaceutical compositions thereof.
It is another object to provide treatment and prevention regimens for androgen and estrogen sensitive diseases which regimens include inhibiting activity of type 3 or type 5 17&bgr;-hydroxysteroid dehydrogenase.
In one embodiment, the invention provides a method of inhibiting activity of type 5 17&bgr;-hydroxysteroid dehydrogenase comprising administering to a patient in need of such treatment a therapeutically effective amount of an inhibitor of type 5 17&bgr;-hydroxysteroid dehydrogenase having the molecular structure:
wherein the dotted line is optional pi bond;
wherein A is selected from the group consisting of straight or branched C
1
-C
4
alkyl, —OR
c
(R
c
being a C
1
-C
8
alkyl radical), and —N(R
d
)R
e
(R
d
and R
e
being independently hydrogen or C
1
-C
8
alkyl or aryl), and unsaturated analogs of any of the foregoing definitions for substituent A;
wherein R
1
is selected from the group consisting of hydrogen and methyl;
wherein R
6
is selected from the group consisting of hydrogen, and halogen, and C
1
-C
8
alkyl;
wherein R
a
is selected from the group consisting of straight or branched C
1
-C
8
alkylene, C
3
-C
7
cycloalkylene; and
R
b
is selected from the group consisting of hydrogen, substituted or unsubstituted phenyl, C
2
-C
10
acyl, C
2
-C
10
acyloxy, C
2
-C
10
alkoxycarbonyl, and halogen;
provided that when A is methyl, R
a
and R
b
together have at least two carbon atoms, and R
1
is methyl.
It is preferred that the optional pi bond at 6 is present that R
6
is methyl, that R
a
is C
1
-C
6
alkylene or that A is either methyl or —N(R
d
)R
e
.
It is also preferred when wherein A is —N(R
d
)R
e
that R
d
is methyl or that R
e
is C
1
-C
6
alkyl or C
7
-C
12
phenyl alkyl.
In another embodiment, the invention provides a method of inhibiting activity of type 5 17&bgr;-hydroxysteroid dehydrogenase comprising administering to a patient in need of such treatment a therapeutically effective amount of an inhibitor of type 5 17&bgr;-hydroxysteroid dehydrogenase having the molecular structure:
wherein the dotted line is an optional pi bond;
wherein R
16&bgr;
is selected from the group consisting of hydrogen, fluoro, chloro, C
1
-C
8
alkyl, C
1
-C
8
haloalkyl, a moiety which together with R
16&agr;
is C
4
-C
7
spirocycloalkyl, C
4
-C
7
halospirocycloalkyl, or ═—R′
16
(R′
16
being C
1
-C
3
alkyl) and unsaturated analogs of any of the foregoing definitions of R
16&bgr;
;
wherein R
16&agr;
is selected from the group consisting of hydrogen, C
1
-C
8
alkyl, C
1
-C
8
haloalkyl, a moiety which together with R
16&bgr;
forms C
4
-C
7
spirocycloalkyl, C
4
-C
7
halospirocycloalkyl, or ═—R′
16
(R′
16
being C
1
-C
3
alkyl) and unsaturated analogs of any of the foregoing.;
wherein R
15&agr;
is selected from the group consisting of hydrogen, C
1
-C
4
alkyl, C
1
-C
4
alkenyl and C
1
-C
4
alkynyl;
wherein R
19
is either —H or —CH
3
; and
wherein R
6
is selected from the group consisting of —H, CH
3
, and halo;
provided that R
16&bgr;
, R
16&agr;
, and R
15&agr;
are not simultaneously hydrogen.
It is preferred that R
16&agr;
is a larger substituent than R
16&agr;
, that R
6
is hydrogen, that
Belanger Alain
Gauthier Sylvain
Labrie Fernand
Luu-The Van
Merand Yves
Badio Barbara P.
Endorecherche Inc.
Ostrolenk Faber Gerb & Soffen, LLP
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