Topical antiandrogen for hair loss and other hyperandrogenic...

Details Topical antiandrogen for hair loss and other hyperandrogenic... Topical antiandrogen for hair loss and other hyperandrogenic...

2000-05-25

2004-12-07

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C514S616000

Reexamination Certificate

active

06828458

ABSTRACT:

TECHNICAL FIELD
The field of this invention is methods and compositions for suppressing androgen receptors, particularly cutaneous androgen receptors, for the treatment of androgenic hair effluvium and alopecia.
BACKGROUND
The pathophysiology of both male and female hair loss is not yet understood. Factors ranging from low scalp blood flow, deficiency of nutrients and hair-related vitamins, microbially-driven inflammatory changes and the like have been considered. It is, nevertheless, apparent that one of the most influential factors is androgenic hormones acting on hair follicles in the scalp. Androgenic hormones promote growth of the beard and of body hair throughout life. The growth of scalp hair also depends on androgenic hormones, but only in early life. With increasing age, androgenic hormones switch from promoting growth of scalp hair to promoting its loss, known as androgenic effluvium and alopecia. In hirsutism and acne vulgaris, an excess of cutaneous androgenic hormones was shown to be the major factor in those complex syndromes.
The androgenic hormones act via androgenic receptors, a cellular protein transcription factor which interacts with a specific region of DNA. Testosterone and its much more potent analog 5-alpha-dihydrotestosterone (DHT) must bind to androgenic receptors first to become active. Scalp androgenic hormones are derived either from the systemic circulation and/or synthesized in the skin and have been shown to bind to androgenic receptors located in the hair follicles.
Systemic antiandrogens, steroidal or nonsteroidal, are compounds which generally are administered orally. Developed to block androgenic hormones from binding to androgenic receptors, they are used primarily for the treatment of prostate cancer and of certain systemic hyperandrogenic conditions. Systemic antiandrogens are stable in vivo and block all androgenic receptors indiscriminately, thus inducing a number of side effects such as loss of libido and of male sexual functions. Skin disorders in otherwise healthy males thus cannot be treated by systemic antiandrogens given orally, nor can they be given topically, since those that are currently in use are absorbed from the skin.
The use of systemic antiandrogens such as the steroids cyproterone acetate, chlormadinone acetate and spironolactone was proposed for treatment of women suffering from androgenic effluvium and alopecia but concerns for side effects call for clinical studies (Diamanti-Kandarakis,
Current Pharm Des,
1999 September, 5(9): 707-23). There are other limitations: It is known that at least in males chronically treated with systemic antiandrogens, the resulting extended androgenic receptor blockade leads to mutation of the androgen receptors, and that the mutated receptors attain the capability of being activated by other substances such as various steroidal metabolites, progestins and estrogens, insulin-like growth factor, epidermal growth factor and keratinocyte growth factor and neuroendocrine transmitters such as serotonin. It has also been shown that the androgenic receptor blockade amplifies synthesis of the androgenic receptor gene. It is apparent therefore that therapy of hyperandrogenic skin afflictions in women using currently available systemic antiandrogens is not ideal and that in men it would not be acceptable at all.
For the treatment of androgenic effluvium and alopecia, the state of therapeutic art is the topical Minoxidil (an antihypertensive drug) and its derivatives, such as aminexil. Minoxidil has been observed to arrest male hair loss, and to an extent, promote regrowth, but only in the vertex scalp; the activity is tentatively explained among others as activation of prostaglandin endoperoxide synthase-1, increase of local blood flow, suppression of bacterial infection and/or a modification of androgenic hormone metabolism in the dermal papilla. (Michelet, et al.
Journal of Investigative Dermatology,
1997 February, 108(2): 205-9; Pirard-Franchimont, et al.
Dermatology,
1998; 196 (4): 474-7; Sato, et al.
Journal of Dermatological Science,
1999 February 19(2): 123-5).
Finasteride (Scow, et al.
American Family Physician,
1999 April 15, 59(8): 2189-94, 2196) has also been used for the treatment of androgenic effluvium and alopecia. Taken orally and daily, it suppresses systemic conversion of testosterone to dihydrotestosterone (DHT), thus reducing overall androgen activity, including in the scalp. The studies indicate that about half of the men treated achieved slight to moderate improvement of effluvium in the anterior mid scalp and in approximately one-half, the effluvium was arrested. Various side effects including loss of libido and of erectile function were reported which disappeared after drug withdrawal. (Kaufman, et al.
Journal of the American Academy of Dermatology.
1998 October, 39 (4 Pt. 1): 578-89). No studies however are yet available which prove unequivocally that a long term systemic manipulation of hormonal balance with finasteride is harmless.
Popular traditional Chinese medicine utilized topical treatment of androgenic effluvium and alopecia with an extract from
Polygonum cuspidatum,
an asian cane which contains resveratrol. Phytoestrogens and other substances are known to interfere with androgenic receptors. (Mitchell, et al.
Cancer Res.
(1999) 58:5892-5.
It therefore would be of interest to develop an antiandrogen which would suppress or eliminate rather than only block androgenic receptors in a defined topical location, and which would not be irritating or resorbable from the skin. Such a compound would be useful in the therapy of androgenic hormones-dependent cutaneous afflictions.
Relevant Literature
A patent application has been filed for antiandrogens, whose activity was found, rather than blocking, suppressed or even eliminated the androgen receptor in a concentration and time dependent fashion. (Sovak, M. S.; Bressi, J. C.; Douglas, J.; Campion, B.; Wrasidlo, W. Androgenic Directed Compositions, U.S. application Ser. No. 09/215,351, 1998)
U.S. Pat. No. 5,656,651 and WO97/00071, and references cited therein, describe anti-androgenic directed compositions based on phenyldimethylhydantoins, where the phenyl group is substituted with a trifluoromethyl group and either a cyano or nitro group. See also, Battmann et al.,
J. Steroid Biochem. Molec. Biol.
64:103-111 (1998); Cousty-Berlin, ibid 51:47-55 (1994); and Battmann et al., ibid 48:55-60 (1994), for a description of analogous compounds and their activity. For other compounds having the substituted phenyl moiety, see U.S. Pat. Nos. 4,636,505 and 4,880,839, and EP 0 100 172. For discussions about the activities of androgens, see Kuil and Brinkmann,
Eur. Urol.
29:78-82 (1996); Kondo et al.,
Prostate
29:146-152 (1996), and Simard, et al., Urology 49:580-589 (1997). For discussions about alopecia and its relationship with androgens, see Kaufman,
Dermatologic Clinics
14:697-711 (1996); Toney et al.,
J. Steroid Biochem. Molec. Biol.
60:131-136 (1997); Brouwer et al.,
J. of Dermatology
137:699-702 (1997); and Shapiro and Price
Dermatologic Clinics
16341-356 (1998).
SUMMARY OF THE INVENTION
Novel compounds are provided that are 2-hydroxy-3-perfluoroacylamidopropionanilides, where the phenyl is substituted. The compounds inhibit or eliminate skin androgenic receptors without being systemically resorbed and thus find use as a topical cosmetic in a treatment of hair effluvium, alopecia and other skin afflictions dependent on an excess of androgen hormones. The compounds are applied as conventional topical formulations in an amount to reduce the level of androgenic receptors.


REFERENCES:
patent: 4636505 (1987-01-01), Tucker
patent: 4880839 (1989-11-01), Tucker
patent: 5411981 (1995-05-01), Gaillard-Kelly et al.
patent: 5656651 (1997-08-01), Sovak et al.
patent: 5750553 (1998-05-01), Claussner et al.
patent: 6184249 (2001-02-01), Sovak et al.
patent: 6472415 (2002-10-01), Sovak et al.
patent: 0 100 172 (1984-08-01), None
patent: WO 97/00071 (1997-01-01), None
patent: WO 0037430 (2000-06-01), None
Tucker, H.

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