Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-24
2001-01-16
Rose, Shep K. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S859000
Reexamination Certificate
active
06174892
ABSTRACT:
BACKGROUND OF THE INVENTION
Certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, androgenic alopecia which includes female and male pattern baldness, and benign prostatic hyperplasia, are the result of hyperandrogenic stimulation caused by an excessive accumulation of testosterone (“T”) or similar androgenic hormones in the metabolic system. Early attempts to provide a chemotherapeutic agent to counter the undesirable results of hyperandrogenicity resulted in the discovery of several steroidal antiandrogens having undesirable hormonal activities of their own. The estrogens, for example, not only counteract the effect of the androgens but have a feminizing effect as well. Non-steroidal antiandrogens have also been developed, for example, 4′-nitro-3′-trifluoromethyl-isobutyranilide. See Neri, et al.,
Endocrinol.
1972, 91 (2). However, these products, though devoid of hormonal effects, compete with all natural androgens for receptor sites, and hence have a tendency to feminize a male host or the male fetus of a female host and/or initiate feed-back effects which would cause hyperstimulation of the testes.
The principal mediator of androgenic activity in some target organs, e.g. the prostate, is 5&agr;-dihydrotestosterone (“DHT”), formed locally in the target organ by the action of testosterone-5&agr;-reductase. Inhibitors of testosterone-5&agr;-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation in these organs. See especially U.S. Pat. No. 4,377,584 assigned to Merck & Co., Inc., issued Mar. 22, 1983. It is now known that a second 5&agr;-reductase isozyme exists, which interacts with skin tissues, especially in scalp tissues. See, e.g., G. Harris, et al.,
Proc. Natl. Acad. Sci. USA,
Vol. 89, pp. 10787-10791 (November 1992). The isozyme that principally interacts in skin tissues is conventionally designated as 5&agr;-reductase 1 (or 5&agr;-reductase type 1), while the isozyme that principally interacts within the prostatic tissues is designated as 5&agr;-reductase 2 (or 5&agr;-reductase type 2).
Finasteride (17&bgr;-(N-tert-butylcarbamoyl)-4-aza-5&agr;-androst-1-ene-3-one), which is marketed by Merck & Co., Inc. under the tradename PROSCAR®, is an inhibitor of 5&agr;-reductase 2 and is known to be useful for the treatment of hyperandrogenic conditions. See e.g., U.S. Pat. No. 4,760,071. Finasteride is currently marketed in the United States and worldwide for the treatment of benign prostatic hyperplasia. Finasteride's utility in the treatment of androgenic alopecia and prostatic carcinoma is also disclosed in the following documents: EP 0 285,382, published Oct. 5, 1988; EP 0 285 383, published Oct. 5, 1988; Canadian Patent no. 1,302,277; and Canadian Patent no. 1,302,276. The specific dosages exemplified in the above-noted disclosures varied from 5 to 2000 mg per patient per day.
In the treatment of androgenic alopecia, which includes both female and male pattern baldness, and other hyperandrogenic conditions, it would be desirable to administer the lowest dosage possible of a pharmaceutical compound to a patient and still maintain therapeutic efficacy. Applicants have surprisingly and unexpectedly discovered that a low daily dosage of a 50&agr;-reductase 2 inhibitor is particularly useful in the treatment of androgenic alopecia. Furthermore, a low daily dosage of a 5&agr;-reductase 2 inhibitor may also be particularly useful in the treatment of the hyperandrogenic conditions of acne vulgaris, seborrhea, female hirsutism, and polycystic ovary syndrome.
DETAILED DESCRIPTION OF THE INVENTION
The instant invention involves a method of treating and/or reversing androgenic alopecia and promoting hair growth, and methods of treating acne vulgaris, seborrhea, and female hirsutism, which comprises administering to a patient in need of such treatment a 5&agr;-reductase 2 inhibitor in a dosage amount under 5 mgs/day. In one embodiment of this invention, the 5&agr;-reductase 2 inhibitor is administered in a dosage amount of from 0.01 to 3.0 mgs/day. In one class of this embodiment, the 5&agr;-reductase 2 inhibitor is administered in a dosage amount of from 0.05 to 1.0 mg/day, and in a sub-class of this embodiment, the 5&agr;-reductase 2 inhibitor is administered in dosage amounts of about 0.05 to 0.2 mg/day. Illustrating this subclass are dosage amounts of about 0.05, 0.1, 0.15 and 0.2 mg/day. Exemplifying the sub-class are dosages of 0.05 and 0.2 mg/day. Compounds which are inhibitors of 5&agr;-reductase 2 can be determined by employing the assay described below in Example 3.
In a second embodiment of this invention, the method of treating androgenic alopecia comprises administration of 5&agr;-reductase 2 inhibitor compounds which have the structural formula I
or a pharmaceutically acceptable salt thereof wherein:
R
1
is hydrogen, methyl or ethyl;
R
2
is a hydrocarbon radical selected from straight and branched chain alkyl of from 1-12 carbons or monocyclic aryl optionally containing 1 or more lower alkyl substituents of from 1-2 carbon atoms and/or 1 or more halogen (Cl, F or Br) substituents;
R′ is hydrogen or methyl;
R″ is hydrogen or &bgr;-methyl; and
R′″ is hydrogen, &agr;-methyl or &bgr;-methyl.
In one class of this second embodiment, the 5&agr;-reductase 2 inhibitor compounds have the structural formula II
or a pharmaceutically acceptable salt thereof wherein
R
1
is hydrogen, or methyl; and
R
3
is branched chain alkyl of from 4-8 carbons.
Representative compounds that may be employed in the present invention include the following:
17&bgr;-(N-tert-butylcarbamoyl)-4-aza-5&agr;-androst-1-en-3-one,
17&bgr;-(N-isobutylcarbamoyl)-4-aza-5&agr;-androst-1-en-3-one,
17&bgr;-(N-tert-octylcarbamoyl)-4-aza-5&agr;-androst-1-en-3-one,
17&bgr;-(N-octylcarbamoyl)-4-aza-5&agr;-androst-1-en-3-one,
17&bgr;-(N-1,1-diethylbutylcarbamoyl)-4-aza-5&agr;-androst-1-en-3-one,
17&bgr;-(N-neopentylcarbamoyl)-4-aza-5&agr;-androst-1-en-3-one,
17&bgr;-(N-tert-amylcarbamoyl-4-aza-5&agr;-androst-1-en-3-one, and
17&bgr;-(N-tert-hexylcarbamoyl)-4-aza-5&agr;-androst- 1-en-3-one;
and the corresponding compounds wherein the 4-nitrogen is substituted in each of the above named compounds by a methyl or an ethyl radical.
Also included as representative compounds are any of the above indicated compounds having the N-branched chain alkyl substituent replaced by a methyl, ethyl, propyl, i-propyl, butyl, phenyl; 2, 3 or 4 tolyl, xylyl, 2-bromo or 2-chlorophenyl, 2-6-dichloro, or a 2,6-dibromophenyl substituent.
The compounds of formula I and II described above can be synthesized according to procedures well known in the art, and which are described, for example, in U.S. Pat. No. 4,760,071, EP 0 285,382 and EP 0 285 383. The compound finasteride is currently available as a prescription pharmaceutical from Merck & Co. Inc. The synthesis of finasteride is described in U.S. Pat. No. 4,760,071. A further synthesis of finasteride is described in
Synthetic Communications,
30 (17), p. 2683-2690 (1990).
The present invention has the objective of providing methods of treating the hyperandrogenic conditions of androgenic alopecia, including male pattern baldness and female pattern baldness, acne vulgaris, seborrhea, female hirsutism, and polycystic ovary syndrome by systemic, oral, parenteral or topical administration of a 5&agr;-reductase 2 inhibitor in a dosage amount under 5 mg/day, and particularly, from about 0.01 mg/day to 3.0 mg/day, and more particularly 0.05 to 1 mg/day. The invention is further illustrated by dosages of about 0.05 to 0.2 mg/day and specifically dosages of about 0.05, 0.1, 0.15 and 0.2 mg/day. Exemplifying the invention are dosages of 0.05 and 0.2 mg/day. The term “treating androgenic alopecia” is intended to include the arresting and/or reversing of androgenic alopecia, and the promotion of hair growth. Also, a 5&agr;-reductase 2 inhibitor, e.g. finasteride, at a dosage under 5 mgs/day can be used in combination with a potassium channel opener, such as minoxidil or a pharmaceutical
Gormley Glenn J.
Kaufman Keith D.
Stoner Elizabeth
Waldstreicher Joanne
Fitch Catherine D.
Merck & Co. , Inc.
Rose Shep K.
Winokur Melvin
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