Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-07
2003-05-27
Reamer, James H (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S254080, C514S329000
Reexamination Certificate
active
06569872
ABSTRACT:
FIELD OF THE INVENTION
The invention is directed to a method of treating an androgen-dependent disease in mammals, e.g., humans, with antagonists of neurokinin-1 (NK
1
), neurokinin-2 (NK
2
) and/or neurokinin-3 (NK
3
) receptors. The invention further relates to the use of these antagonists for purposes of prophylactic modulation.
BACKGROUND OF THE INVENTION
An androgen-dependent disease is one which is exacerbated by, or caused by, excessive, inappropriate or unregulated androgen production. Examples of such diseases in men include, but are not limited to, benign prostatic hyperplasia (BPH), metastatic prostatic carcinoma, testicular cancer, androgen dependent acne, male pattern baldness and precocious puberty in boys. Examples of such diseases in women include, but are not limited to, hyperandrogenism, hirsutism, virilization, polycystic ovary syndrome (PCOS), HAIR-AN syndrome (hyperandrogenism, insulin resistance and acanthosis nigricans), ovarian hyperthecosis (HAIR-AN with hyperplasia of luteinized theca cells in ovarian stroma), other manifestations of high intraovarian androgen concentrations (e.g., follicular maturation arrest, atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding, infertility) and androgen-producing tumors (virilizing ovarian or adrenal tumor).
Benign prostatic hyperplasia and prostatic carcinoma are among the most common afflictions of aging men.
Benign prostatic hyperplasia is often treated surgically with a procedure known as transurethral resection of the prostate (TURP). Other surgical procedures performed to release the obstruction of urine include incision or stents. Castration has also resulted in regression of prostatic enlargement. Drug therapy for BPH has included alpha-1 blockers which treat the symptoms of the disease by alleviating obstructive symptoms, but do not affect the underlying cause of the disease, the enlarged prostate gland. Representative alpha-1 blockers used in the treatment of BPH include: prazosin, terazosin, doxazosin, tamsulosin and alfuzosin. These drugs relax prostatic smooth muscle tone, decreasing intraurethral pressure without affecting bladder pressure. Common side effects of these agents are dizziness, headache and fatigue.
Both prostatic carcinoma and BPH have been treated with antiandrogens. A principal mediator of androgenic activity in the prostate is 5&agr;-dihydrotestosterone (DHT), formed locally in the prostate by the action of testosterone-5&agr;-reductase. Inhibitors of testosterone-5&agr;-reductase inhibit the conversion of testosterone (T) to DHT and serve to prevent or lessen symptoms of hyperandrogenic stimulation in the prostate. Non-steroidal antiandrogens such as flutamide and Casodex compete with DHT for androgen receptor sites in the prostrate cells. These non-steroidal antiandrogens do not substantially change sexual potency and libido as the gonadotrophin releasing hormone agonists and progestogens do; however, these non-steroidal antiandrogens often exhibit the undesirable tendency to feminize the male host (gynaecomastia) or initiate feed-back effects which would cause hyperstimulation of the testes.
Luteinizing hormone (LH), under control of Gonadotropin Releasing Hormone (GnRH), is released by the pituitary gland and stimulates the production of androgens by the gonads. Androgens, the principle one being testosterone, are secreted mainly by the testes and, to a lesser degree, by the adrenal cortex and ovary. Suppression of gonadotropin production and/or secretion results in the suppression of androgen production and/or secretion.
Gonadotropin-releasing hormone (GnRH) agonists such as nafarelin, buserelin, goserelin and leuprorelin, reduce the release of luteinizing hormone (LH) by desensitizing the GnRH receptors in the anterior pituitary gland. GnRH agonists are able to reduce the production of testosterone, induce shrinkage of prostate volume and reduce the severity of urinary symptoms of BPH. Unfortunately, these drugs have adverse effects such as impotence and flushing, which discourage a majority of patients from continuing with the drugs. These androgen-suppressing agents are thus of inconsequential significance in BPH treatment, but are of major importance in the treatment of patients with advanced prostatic cancer. These initially can cause increased androgen production before desensitization occurs, which is a major side effect.
Progestogens, such as megestrol acetate, hydroxyprogesterone and medrogestone depress testosterone by inhibiting LH release and blocking androgen receptors, causing a reduction in prostatic volume. Adverse effects such as decreased libido and impotence have limited progestogens from common use in BPH treatment.
Thus, there remains a need for improved therapies for BPH and prostatic carcinoma, as well as other androgen-dependent diseases. There also remains a need for an additional method for the treatment of androgen-dependent diseases which utilizes non-steroidal compounds that possess different pharmacological properties from steroids.
Neurokinin receptors can be found in the nervous system, circulatory system and peripheral tissues of mammals. Consequently, the modulation of these types of receptors have been studied to potentially treat or prevent various mammalian disease states. Representative types of neurokinin receptor antagonists and the disorders that can be treated with them can be found in: U.S. Pat. No. 6,329,401 (2001) (sleep), U.S. Pat. No. 5,760,018 (1998) (pain, inflammation, migraine and emesis), U.S. Pat. No. 5,620,989 (1997) (pain, nociception and inflammation), WO 95/19344 (same), WO 94/13639 (same) and WO 94/10165 (same).
NK
1
and NK
2
receptor antagonists have also been disclosed in U.S. Pat. No. 5,350,852 and WO 94/29309.
WO 00/43008 discloses a method of suppressing gonadotropin and/or androgen production with specific NK
3
receptor antagonists.
SUMMARY OF THE INVENTION
One aspect of the invention provides a method of decreasing in vivo concentrations of androgens to normal or sub-normal levels in a patient suffering from a disease state which is exacerbated by, or caused by excessive, inappropriate or unregulated androgen production or secretion. Another aspect of the invention provides a method of prophylactic androgen modulation.
Another aspect of the invention provides a method of treating a symptom or disorder associated with a production and/or secretion of androgen comprising administering to a patient in need of such treatment a therapeutically effective amount of an antagonist selected from the group consisting of: (a) antagonists of neurokinin-1 (NK
1
), neurokinin-2 (NK
2
) and neurokinin-3 (NK
3
) receptors, (b) antagonists of NK
1
and NK
2
receptors, (c) antagonists of NK
2
and NK
3
receptors, (d) antagonists of NK
1
and NK
3
receptors, (e) antagonists of NK
1
receptors, and (f) antagonists of NK
2
receptors.
Further provided is a method of treating a symptom or disorder associated with a production and/or secretion of androgen, comprising administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antagonist selected from the group consisting of: (a) antagonists of neurokinin-1 (NK
1
), neurokinin-2 (NK
2
) and neurokinin-3 (NK
3
) receptors, (b) antagonists of NK
1
and NK
2
receptors, (c) antagonists of NK
2
and NK
3
receptors, (d) antagonists of NK
1
and NK
3
receptors, (e) antagonists of NK
1
receptors, and (f) antagonists of NK
2
receptors.
Another aspect of the invention is directed to a method of treating a symptom or disorder associated with the production and/or secretion of androgen comprising administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising the antagonist of formula 1 shown below and a pharmaceutically acceptable carrier.
The invention also provides a method of treating a symptom or disorder associated with a production and/or secretion of androgen comprising administering to a
Berardi Mark R.
Cartwright Mark E.
Leach Michael W.
Mirro Elmer J.
Pachter Jonathan A.
Kalyanaraman Palaiyur S.
Kutzenco Allen N.
Reamer James H
Schering Corporation
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