Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-01-28
2002-04-30
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S880000
Reexamination Certificate
active
06380179
ABSTRACT:
The present invention relates to a novel composition useful in the treatment of alopecia female hirsutism or seborrhea or in the prevention of bone metastasis caused by prostatic cancer.
BACKGROUND OF THE INVENTION
Excessive stimulation of androgenic hormones such as dihydrotestosterone (DHT) causes androgen-dependent alopecia (male pattern baldness or the like), acne vulgaris, seborrhea, female hirsutism, benign prostatic hypertrophy and prostatic cancer.
Steroidal anti-androgenic hormones (e.g. female hormone estrogen) are compounds which were found to be capable of treating these symptoms caused by excessive stimulation of androgenic hormones. However, they tend to bring about undesirable activities, for example, feminization, because they themselves have hormonal activity.
On the other hand, nonsteroidal anti-androgenic hormones have also been developed. In spite of being free from hormonal action, they compete with natural androgens for a receptor and therefore have undesirable activities such as feminization of a male fetus in the uterus or of a male, or initiation of a feedback mechanism so as to excessively stimulate the testis.
As 5&agr; reductase acts on testosterone to form dihydrotestosterone (DHT), if the activity of 5&agr; reductase can be inhibited, treatment of symptoms due to excessive stimulation of androgenic hormones without said side effects can be expected.
Human 5&agr; reductase includes two isozymes. It has been elucidated that type I 5&agr; reductase exists in the sebaceous glands of the face and skin, and that type II 5&agr; reductase is distributed in the prostate.
It was expected that strong inhibition of type I 5&agr; reductase existing in the hair follicle would alleviate male panem baldness. The effects of MK386, a selective inhibitor of type I 5-&agr;-reductase, were evaluated using a monkey which was a model animal of male pattern baldness. As a result, the DHT level in the blood showed a 30 to 40% decrease, but such effectiveness of MK 386 was not recognized (J. Invest. Dermatol., 104, 658(1995)).
Administration of Finasteride, which is a selective inhibitor of type II 5&agr;-reductase, to the model animal at a dose of 1 mg/kg decreased the DHT level in blood by 60 to 70%, however it was unexpectedly recognized that it was effective in the treatment of baldness (J. Clin. Endocrinol. Metabol., 79, 991(1994)).
In fact, the effects of Finasteride on human baldness have been recognized by a clinical test. The inhibition of a factor which participates in the reduction in the size of hair follicles results in such effects and it is presumed to depend on the DHT level in the blood. In addition, it has been found as a result of recent clinical tests that the strength of lowering the DHT level in the blood mainly depends on the strength of the inhibitory activity against type II 5&agr; reductase, and that better results can be obtained by use of an inhibitor of type I 5&agr; reductase in combination with that of type II 5&agr; reductase (J. Clin. Endocrinol. Metabol., 81, 2942-2947(1996)).
Also in the treatment of female hirsutism or seborrhea, a compound having inhibitory activity against type I 5&agr;-reductase and that against type II 5&agr;-reductase is considered to become superior, as a remedy, to a compound having only inhibitory activity against type II 5&agr;-reductase. In order to find a more effective medicament for alopecia, female hirsutism or seborrhea, a compound which inhibits type II 5&agr;-reductase more strongly than Finasteride and at the same time strongly inhibits type I 5&agr;-reductase has been required.
Type II 5&agr;-reductase is distributed in the prostate, so a compound having strong inhibitory activity against type II 5&agr;-reductase is effective for the treatment of prostatic cancer, but it has been found recently that during the development of prostatic cancer and bone metastasis, type I 5&agr;-reductase is in the active form [Japanese Patent Application (kokai) No. Hei 8-277220]. The compound as described above which is capable of inhibiting both of type I and type II 5&agr;-reductases is also expected to be useful in the prevention and treatment of prostatic diseases.
The compound (I) of the present invention has been disclosed to have strong inhibitory activity against prostatic enzymes [Japanese Patent Application (kokai) Hei 5-326931. It is reasonable to expect inhibitory activity against type II 5&agr;-reductase from the inhibitory activity against prostatic enzymes. However it is impossible to expect inhibitory activity against type I 5&agr;-reductase, because type I 5&agr;-reductase is not distributed in the prostate.
SUMMARY OF THE INVENTION
The present inventors carried out an extensive investigation for many years on the synthesis of derivatives having inhibitory activity against testosterone 5&agr;-reductase and the pharmacological activity of the derivatives. As a result, it has been found that some compounds having a specific structure strongly inhibit type II 5&agr;-reductase and moreover strongly inhibit type I 5&agr;-reductase, and therefore they exhibit strong DHT blood level lowering activity which has not been available so far among known type II selective 5&agr;-reductase inhibitors, and that they are useful in the treatment of alopecia, female hirsutism or seborrhea or in the prevention of the bone metastasis caused by prostatic cancer.
The present invention provides a novel composition useful in the treatment of alopecia, female hirsutism or seborrhea or in the prevention of bone metastasis caused by prostatic cancer. In another aspect, the present invention provides a use of said compound for the preparation of a composition for the treatment of alopecia, female hirsutism or seborrhea or a composition for the prevention of bone metastasis caused by prostatic cancer.
In still another aspect, the present invention provides a method for treating alopecia, female hirsutism or seborrhea or for preventing bone metastasis caused by prostatic cancer, which comprises administering a therapeutically effective amount of said compound to a warm-blooded animal in need of such treatment.
The novel composition for the treatment of alopecia of the present invention, female hirsutism or Seborrhea or for the prevention of bone metastasis caused by prostatic cancer comprises, as an active ingredient, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, preferably N-[1-methyl-1-(4-methoxyphenyl)ethyl]-3-oxo-4-aza-5&agr;-androst-1-ene-17&bgr;-carboxamide.
The inventive method administers a compound represented by formula (I) or a pharmaceutically acceptable salt or ester or hydrate thereof for the treatment of alopecia, female hirsutism or seborrhea or the prevention of bone metastasis caused by prostatic cancer. Preferably N-[1-methyl-1-(4-methoxyphenyl)ethyl]-3-oxo-4-aza-5&agr;-androst-1-ene-17-&bgr;-carboxamide for the preparation of said composition is used.
(wherein, R
1
and R
2
are the same or different from each other and each represents a hydrogen atom, a hydroxyl group, a protected hydroxyl group or a lower alkoxy group).
In the formula (I), the term “lower alkoxy group” means a straight chain or branched chain C
1-6
alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy or 2,3-dimethylbutoxy, of which a straight or branched C
1-4
alkoxy group is preferred, and a methoxy group is more preferred.
The term “alopecia” means male pattern baldness and female head alopecia.
Since compound (I) can form a salt, the term “pharmaceutically acceptable salts” means the salts of the compound (I) of the present invention which can be converted to salts thereof, examples of such salts preferably include alkali metal salts such as a sodium salt, a potassium salt and a lithium salt, alkaline ear
Doi Hiromi
Hamada Takakazu
Kojima Koichi
Yoshioka Hideyuki
Yoshioka Mitsuko
Doi Hiromi
Frishauf, Holtz Goodman, Langer & Chick, P.C.
Nguyen Helen
Sankyo Company Limited
Webman Edward J.
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