Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2001-06-21
2002-07-02
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S182000, C552S515000, C552S530000, C552S532000
Reexamination Certificate
active
06413951
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to 20-fluoropregna-5,17(20)-diene-3&bgr;,21-diol, 20-fluoro-pregna-5,17(20)-dien-3&bgr;-ol and related compounds, to processes for their preparation, and to compositions incorporating these compounds as well as the use of these compounds in the treatment of conditions which would be affected by inhibition of C
17,20
lyase and/or 5&agr;-reductase, including androgen and estrogen mediated or dependent disorders, such as, for example benign prostatic hyperplasia; dihydrotestosterone-mediated disorders such as, for example, acne; estrogen dependent breast cancer and androgen mediated prostatic cancer. The present invention provides a novel series of compounds which also disable the operation of C
17
-hydroxylase; thus, disorders that are characterized by an oversynthesis of cortisol can also be treated by the compounds of the invention. For example, hypokalemia, metabolic alkalosis, polydipsia, polyurea, Cushing's syndrome and hypertensive conditions.
2. Description of the Art
The enzyme steroid C
17,20
lyase cleaves the 17-20 carbon-carbon bond in steroids having a two carbon side chain at the 17&bgr;-carbon position to form important precursor molecules for the formation of testosterone, 5&agr;-dihydrotestosterone and the estrogens, principally estrone and estradiol. Compounds which inhibit this enzyme would thus serve to inhibit the formation of the indicated precursors and thereby be useful in the treatment of various androgenic as well as estrogenic disorders. A treatment incorporating such enzymatic inhibitors is not limited to the origin of the precursor molecule, such as various organ ablation techniques which are currently known. For example, while orchiectomy will effectively reduce gonadal androgen, it will have not have significant effect upon adrenal androgen production. Moreover, such an enzymatic treatment is a much more focused treatment in that it is directed to the immediate hormonal imbalance believed responsible for the condition, as opposed to a broad spectrum remedy which not only affects the particular symptom, but causes permanent endocrine deficits necessitating life-long dependency on replacement therapy.
It is further known that certain types of breast cancers are estrogen dependent. Adrenalectomy, ovariectomy and hypophysectomy have been employed as well as non-surgical techniques resulting in tumor regressions. It has been shown that human patients with advanced breast cancer, who are administered estrogen biosynthesis enzyme inhibitors, show dramatically reduced plasma estradiol levels and improved therapeutic effects, at least as effective as adrenalectomy. [Van Wauve, J. and Janssen, P. A. J.,
J. Med. Chem
. 1989, 32, 2231-2239].
Prostatic cancer, or neoplastic tissue disorders which originate in the parenchymal epithelium of the prostate, is one of the most common malignancies among men, and exhibits one of the highest cancer-specific deaths of all malignant carcinomas. It is known that patients with metastatic prostate cancer respond positively to hormonal therapy. It is reported by Cookson and Sarosdy that androgen ablation has had a positive, beneficial response for as high as 60% to 80% of all patients tested. [Cookson, C. S. and Sarosdy, M. F.,
South Med. J
. 1994, 87, 1-6].
More specifically, C
17,20
lyase inhibitors would be useful in the treatment of hormonal dependent prostatic carcinorna, prostatic hyperplasia, virilism, congenital adrenal hyperplasia due to 21-hydroxylase deficiency, hirsutism, hormonal dependent breast cancer, polycystic ovarian syndrome correlated with elevated C
17,20
lyase activity as well as other neoplastic tissue disorders such as endometrial, hepatocellular and adrenal carcinomas.
The enzyme steroid 5&agr;-reductase, present in mammalian tissues including skin, male genitalia and the prostate, catalyzes the conversion of testosterone (17&bgr;-hydroxyandrost-4-en-3-one) into dihydrotestosterone or DHT (17&bgr;-hydroxy-5&agr;-androstan-3-one), which is also known as stanolone. DHT is a more potent androgen than testosterone, and acts as an end-organ effector in certain tissues, particularly in mediating growth. DHT formation can occur in certain tissues themselves by the action of 5&agr;-reductase. The conversion of testosterone to DHT itself can be associated with various androgenic disorders, especially when DHT levels build up to excessive amounts. For example, high levels of DHT in the skin has been associated in the pathogenesis of acne, including acne vulgaris. In the treatment of androgen mediated or androgen dependent disorders, such as acne, benign prostatic hyperplasia and prostatic cancer, including hormonal dependent carcinoma, the inhibition of DHT would be highly desirable.
Agents that have the ability to inhibit both C
17,20
lyase and 5&agr;-reductase would not only inhibit DHT production, but also testosterone formation. In inhibiting the principal androgenic steroidal hormones, such compounds would have enhanced utility in the treatment of androgen mediated or dependent disorders.
The enzyme C
17
hydroxylase catalyzes the C
17
hydroxylation of steroid substrates during the biosynthesis of cortisol. As C
17,20
lyase and C
17
hydroxylase are the same active site of the same enzyme, the inhibition of one usually results in the inhibition of the other. Cortisol excess results in a syndrome characterized by hypokalemia, metabolic alkalosis, polydipsia, polyuria, Cushing's syndrome and hypertensive conditions. Inhibition of cortisol synthesis via C
17
hydroxylase would, therefore, have a beneficial therapeutic effect for the treatment of these disorders or conditions.
SUMMARY OF THE INVENTION
More particularly, the present invention is directed to a group of compounds, and to their pharmaceutically acceptable salts, of the formula:
wherein:
R
1
is H or C
1-4
alkyl;
R
2
is H or C
1-4
alkyl;
R
3
is H, chloro, nitro, amino or C
1-4
alkyl;
R
4
is H or C
1-4
alkyl;
R
5
is H or C
1-4
alkyl;
R
6
is H or methyl;
R
7
is H or methyl;
R
8
is H or methyl;
R
9
is H or methyl;
or R
8
and R
9
taken together is oxo;
R
10
is H or methyl;
R
11
is H;
R
12
is hydroxy;
or R
11
and R
12
taken together is oxo;
X is H, hydroxy or methoxy;
with the proviso that when:
a) R
11
is H and R
12
is hydroxy, bond C
4,5
is a single bond, bond C
5,6
is a double bond and bond C
15,16
is optionally a single bond or a double bond, and
b) R
11
and R
12
taken together is oxo, bond C
4,5
is a double bond, bond C
5,6
is a single bond, and bond C
15,16
is a single bond.
Another embodiment of the invention provides use of the compounds of the invention as inhibitors of C
17,20
lyase and 5&agr;-reductase for the treatment of androgen or estrogen mediated or dependent disorders such as breast cancer, polycystic ovarian syndrome, prostatic hyperplasia, prostatic cancer, virilism, hirsutism, and acne.
In another embodiment, the invention provides use of the compounds of the invention for the treatment of Cushing's syndrome.
In yet another embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.
In another embodiment, the compounds of the invention may be administered in combination with other effective treatments for enhanced therapeutic effect. For example, in the treatment of androgen-dependent disorders, including prostatic cancer, flutamide, a known androgen receptor antagonist, may be used in combination with compounds of the invention.
A preferred embodiment of the invention are compounds wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
and X are hydrogen, R
10
is methyl, R
12
is hydroxy, bond C
4,5
and bond C
15,16
are each a single bond and bond C
5,6
is a double bond.
A most preferred embodiment of the invention are compounds wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
and R
11
are hydrogen, R
10
is methyl, X and R
12
are each hydroxy, bond C
Burkhart Joseph P.
Gates Cynthia A.
Peet Norton P.
Weintraub Philip M.
Aventis Pharmaceuticals Inc.
Badio Barbara P.
Martin Lawrence L.
Nesbitt Stephen L.
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