Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-24
2004-02-24
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S337000, C514S453000, C514S455000, C514S457000, C514S532000, C514S544000, C514S557000, C514S558000, C514S617000, C514S622000, C514S646000, C514S655000, C514S678000, C514S680000, C514S681000, C514S682000, C514S683000, C514S679000, C514S720000, C514S729000, C514S731000, C514S732000
Reexamination Certificate
active
06696484
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates generally to compounds, compositions and methods regulating the action and function of androgens and other steroid hormones by modulating the activity of steroid-reductases, including isozymes of &agr;-reductases.
BACKGROUND OF THE INVENTION
In some of the androgen-sensitive organs, such as the prostate and skin, testosterone (T) is converted to a more active metabolite 5&agr;-dihydrotestosterone (DHT) by 5&agr;-reductase (Anderson and Liao, 1968; Bruchovsky and Wilson, 1968). Other substrates of 5&agr;-reductases are also converted to reduce products that may have specific properties. Inhibition of 5&agr;-reductase represents a unique approach for developing therapeutic methods for androgen-dependent diseases, such as benign prostatic hyperplasia, breast and prostatic cancer, skin disorders, seborrhea, common baldness, hirsutism, and hidradenitis suppurative. Various compounds have been shown to inhibit 5&agr;-reductase activity (Liang and Liao, 1992; Hirsch et al., 1993; Russell and Wilson, 1994; Liao and Hiipakka, 1995). Finasteride (Proscar), a 5&agr;-reductase inhibitor, lowers the level of DHT in serum and the prostate, reduces prostate volume and increases urinary flow in some patients (Stoner E. Finasteride Study Group, 1992). Certain aliphatic unsaturated fatty acids, such as &ggr;-linolenic acid (Liang and Liao, 1992) and catechin-3-gallates (Liao and Hiipakka, 1995), can inhibit 5&agr;-reductase activity of liver and prostate of rats and humans in vitro.
5&agr;-Reductase is found in many organs (Russell and Wilson, 1994; Hiipakka et al., 1993) including the sebaceous gland of hamsters (Takayasu and Adachi, 1972) and human hair follicles (Randall, 1994). Two 5&agr;-reductase isozymes have been identified in rats and humans (Russell and Wilson, 1994). The type 1 isozyme predominates in rat tissues such as liver, kidney, brain, and lung, whereas the type 2 enzyme is more abundant in rat testis and epididymis. Both isozymes are found in skins of the neonate, but the type 1 isozyme is the major form expressed in the skin after puberty. The type 1 isozyme is also expressed in balding scalp. The possibility that the type 2 isozyme plays a unique role in skin and hair growth cannot be excluded. Finasteride, a 4-azasteroid, is a competitive inhibitor of 5&agr;-reductases and has an affinity 30-fold higher for isozyme 2 than for isozyme 1 (Russell and Wilson, 1994). In contrast, the green tea catechins, epicatechin-3gallate and epigallocatechin-3-gallate are more effective inhibitors of the type 1 enzyme and &ggr;-linolenic acid inhibits both isozymes equally well (Liao and Hiipakka, 1995).
In the stumptail macaque, a monkey model of androgenic alopecia, finasteride given orally prevents frontal baldness (Diani et al, 1992). The paired hamster flank organs, one on each side of the costovertebral angle, are highly sensitive to androgen stimulation. Topical application of &ggr;-linolenic acid suppresses only the androgen-dependent growth of the treated hamster flank organ without showing systemic effects on the contralateral flank organ and this effect is very likely due to local inhibition of 5&agr;-reductase.
Uses of androgens known to the medical arts include, for example, treatment of hypogonadism and anemia. The abuse of androgens among athletes to enhance performance is well known. Androgens are also known to promote the development of benign prostatic hyperplasia (BPH), prostate cancer, baldness, acne, obesity and undesirable lipid and steroid profiles in blood and organs. Approximately 70% of males in the U.S. over the age of 50 have pathological evidence of BPH. Prostate cancer is the second leading cause of cancer death in males in the U.S. Male-pattern baldness can start as early as the teens in genetically susceptible males, and it has been estimated to be present in 30% of Caucasian males at age 30, 40% of Caucasian males at age 40, and 50% of Caucasian males at age 50. Further, acne is the most common skin disorder treated by physicians. In women, hirsutism is one of the hallmarks of excessive androgen. The ovaries and the adrenal are the major sources of androgen in women.
In men, the major androgen circulating in the blood is testosterone. About 98% of the testosterone in blood is bound to serum proteins (high affinity binding to sex-steroid binding globulin and low affinity binding to albumin), with only 1-2% in free form. The albumin-bound testosterone, the binding of which is readily reversible, and the free form are considered to be bioavailable, and account for about 50% of total testosterone. Testosterone enters target cells apparently by diffusion. In the prostate, seminal vesicles, skin, and some other target organs, it is converted by a NADPH-dependent 5&agr;-reductase to a more active metabolite, 5&agr;-DHT. 5&agr;-DHT then binds an androgen receptor (AR) in target organs. The 5&agr;-DHT-receptor complexes interact with specific portions of the genome to regulate gene activities (Liao et al., 1989). Testosterone appears to bind to the same AR, but it has a lower affinity than 5&agr;-DHT. In tissues such as muscle and testes, where 5&agr;-reductase activity is low, testosterone may be the more active androgen.
The difference between testosterone and 5&agr;-DHT activity in different androgen-responsive tissues is further suggested by findings in patients with 5&agr;-reductase deficiency. Males with 5&agr;-reductase deficiency are born with female-like external genitalia. When they reach puberty, their plasma levels of testosterone are normal or slightly elevated. Their muscle growth accelerates, the penis enlarges, voice deepens, and libido toward females develops. However, their prostates remain non-palpable, they have reduced body hair, and they do not develop acne or baldness.
The findings in 5&agr;-reductase deficient patients suggest that inhibitors of 5&agr;-reductase would be useful for the treatment of prostatic cancer, BPH, acne, baldness, and female hirsutism. Clinical observations and animal experiments have indicated that spermatogenesis, maintenance of libido, sexual behavior, and feedback inhibition of gonadotropin secretion do not require the conversion of testosterone to 5&agr;-DHT. This is in contrast to other hormonal therapies which abolish the actions of both testosterone and 5&agr;-DHT.
Treatment of androgen-dependent skin and prostatic diseases by 5&agr;-reductase inhibitors would be expected to produce fewer side effects than the presently available hormonal therapies. These include castration, estrogen therapy, high doses of superactive gonadotropin-releasing hormone such as Luprolide, and the use of competitive antiandrogens which inhibit AR binding of testosterone and 5&agr;-DHT, such as flutamide, cyproterone acetate and spironolactone. The long term efficacy of competitive antiandrogens is also compromised by their block of the androgenic feedback inhibition of gonadotropin secretion. This increases testicular secretion of testosterone. The higher level of testosterone eventually overcomes the action of the antiandrogen.
Excessive 5&agr;-DHT is implicated in certain androgen-dependent pathological conditions including BPH, acne, male-pattern baldness, and female idiopathic hirsutism. It has been shown that 5&agr;-reductase activity is reported to be higher in hair follicles from the scalp of balding men than that of non-balding men.
Since normal or slightly elevated plasma levels of testosterone in 5&agr;-reductase deficient males produce beneficial effects, it is desirable to provide agents that inhibit particular androgen action while maintaining normal testosterone levels.
BRIEF SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical compositions and methods for treating androgen related disorders. The pharmaceutical compositions may include a 5&agr;-reductase inhibitor, such as natural and synthetic flavanoids, catechols, curcumin-related substances, quinones, catechins, particularly epigallocatechin derivatives, fatty acids, and the salts, es
Hiipakka Richard
Liao Shutsung
Mahoney Joseph A.
Mayer Brown Rowe & Maw LLP
Owens Amelia
Rebman Christine M.
University of Chicago Office of Technology and Intellectual Prop
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