Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1994-12-27
2001-07-31
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06268376
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is concerned with the use of 17&bgr;-N-monosubstituted-carbamoyl-4-aza-5&agr;-androst-1-en-3-one compounds as testosterone-5&agr;-reductase inhibitors for the prevention of prostatic carcinoma.
DESCRIPTION OF THE PRIOR ART
There is no drug which is known to prevent prostatic cancer to date. Most forms of androgen withdrawal result in sexual dysfunction and gynecomotia making them unacceptable for prevention therapy.
It is further well known in the art that certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, male pattern baldness and benign prostatic hypertrophy, are the result of hyperandrogenic stimulation caused by an excessive accumulation of testosterone or similar androgenic hormones in the metabolic system. It is also established that androgens play an important role in prostatic carcinoma. Boys castrated prior to puberty or with a metabolic deficiency of androgens do not develop prostatic cancer. 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 anti-androgens have also been developed, for example, 4′-nitro-3′-trifluoromethyl-isobutyranilide. See Neri et al., Endo., Vol. 91, No. 2 (1972). However, these products, though devoid of hormonal effects, are peripherally active, competing with the natural androgens for receptor sites, and hence have a tendency to feminize a male host or the male fetus of a female host.
It more recently became known in the art that the principal mediator of androgenic activity in some target organs is 5&agr;-dihydrotestosterone, and that it is formed locally in the target organ by the action of testosterone-5&agr;-reductase. It therefore has been postulated and demonstrated that inhibitors of testosterone-5&agr;-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation. Nayfe et al., Steroids, 14, 269 (1969) demonstrated in vitro that methyl 4-androsten-3-one-17&bgr;-carboxylate was a testosterone-5&agr;-reductase inhibitor. Then Voigt and Hsia, Endocrinology, 92, 1216 (1973), Canadian Pat. No. 970,692, demonstrated that the above ester and the parent free acid, 4-androsten-3-one-17&bgr;-carboxylic acid are both active inhibitors of testosterone-5&agr;-reductase in vitro. They further demonstrated that topical application of either testosterone or 5&agr;-dihydrotestetone caused enlargement of the female hamster flank organ, an androgen dependent sebaceous structure. However, concommitant administration of 4-androsten-3-one-17&bgr;-carboxylic acid or its methyl ester inhibited the response elicited by testosterone but did not inhibit the response elicited by 5&agr;-dihydrotestosterone. These results were interpreted as indicating that the compounds were antiandrogenic by virtue of their ability to inhibit testosterone-5&agr;-reductase.
A number of 4-aza steroid compounds are known. See, for example, U.S. Pat. Nos. 2,227,876; 3,239,417; 3,264,301; and 3,285,918; French Pat. No. 1,465,544; Doorenbos and Solomons, J. Pharm. Sci. 62, 4, pp. 638-640 (1973); Doorenbos and Brown, J. Pharm. Sci., 60, No. 8, pp. 1234-1235 (1971); and Doorenbos and Kim, J. Pharm. Sci. 63, 4, pp. 620-622 (1974).
In addition, U.S. Pat. Nos. 4,377,584, 4,220,775, 4,760,071, 4,859,681 and 5,049,562 of Rasmusson et al. describe a group of 4-aza-17&bgr;-substituted-5&agr;-androstan-3-ones which are said to be useful in the treatment of hyperandrogenic conditions. However, none of the cited references suggest that any of the novel 17&bgr;N-(monosubstituted) carbamoyl-4-aza-5&agr;-androst-1-en-3-ones of the present invention would have utility in preventing prostatic cancer.
DESCRIPTION OF THE INVENTION
The present invention is concerned with preventing prostatic cancer in humans, who are asymptomatic for the disease by treating the patients with 17&bgr;-N-(monosubstituted)-carbamoyl-4-aza-5&agr;-androst-1-en-3 -one compounds. By the term “asymptomatic” as used herein, is meant that overt signs of the disease are not present, or indicated, e.g. lumps or cysts on the prostate wall. However, the patient may or may not have elevated levels of prostate specific antigen (PSA) at the start of therapy, due to the concomitant condition of benign prostatic hyerplasia.
There is no other known way to achieve this with acceptable side effects. The compounds described herein, and specifically finasteride, i.e., 17&bgr;-(N-tert-butylcarbamoyl)-4-aza-5&agr;-androst-1-en-3-one, will lower DHT to castrate levels without lowering testosterone levels and will, therefore, not produce undesirable sexually related side effects. A daily dosage of 1-10 mg p.o. (oral) per person of finasteride will prevent men from developing prostatic cancer.
The present invention is concerned with compounds of the formula:
wherein
R
1
is hydrogen, methyl or ethyl.
R
2
is a hydrocarbon radical selected from straight or branched chain alkyl, cycloalkyl, or aralkyl 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.
R″′ is hydrogen, &agr;-methyl or &bgr;-methyl.
A preferred embodiment of the compounds applicable in the process of our invention is represented by the formula:
wherein
R
1
is hydrogen, methyl or ethyl, and
R
3
is branched chain alkyl, cycloalkyl, or aralkyl of from 4-10 carbons.
Representative compounds of the present invention include the following:
17&bgr;-(N-tert-amylcarbamoyl-4-aza-5&agr;-androst-1-en-3-one,
17&bgr;-(N-tert-hexylcarbamoyl)-4-aza-5&agr;-androst-1-en-3-one.
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-2-adamantylcarbamoyl)-4-aza-5&agr;-androst-1-en-3-one,
17&bgr;-(N-1-adamantylcarbamoyl)-4-aza-5&agr;-androst-1-en-3-one,
17&bgr;-(N-2-norbornylcarbamoyl)-4-aza-5&agr;-androst-1-en-3-one,
17&bgr;-(N-1-norbornylcarbamoyl)-4-aza-5&agr;-androst-1-en-3-one,
17&bgr;-(N-phenylcarbamoyl)-4-aza-4-methyl-5&agr;-androst-1-en-3-one,
17&bgr;-(N-benzylcarbamoyl)-4-aza-4-methyl-5&agr;-androst-1-en-3-one,
17&bgr;-(N-tert-amylcarbamoyl-4-aza-4-methyl-5&agr;-androst-1-en-3-one,
17&bgr;-(N-tert-hexylcarbamoyl)-4-aza-4-methyl-5&agr;-androst-1-en-3-one,
17&bgr;-(N-tert-butylcarbamoyl)-4-aza-4-methyl-5&agr;-androst-1-en-3-one,
17&bgr;-(N-isobutylcarbamoyl)-4-aza-4-methyl-5&agr;-androst-1-en-3-one,
17&bgr;-(N-tert-octylcarbamoyl)-4-aza-4-methyl-5&agr;-androst-1-en-3-one,
17&bgr;-(N-octylcarbamoyl)-4-aza-4-methyl-5&agr;-androst-1-en-3-one,
17&bgr;-(N-1,1-diethylbutylcarbamoyl)-4-aza-4-methyl-5&agr;-androst-1-en-3-one,
17&bgr;-(N-neopentylcarbamoyl)-4-aza-4-methyl-5&agr;-androst-1-en-3-one,
and the corresponding compounds wherein the 4-hydrogen substituent is replaced in each of the above named compounds by a hydrogen or an ethyl radical and vice versa.
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, benzyl, 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 of the present invention are prepared by a method starting with the known steroid ester of the formula:
17&bgr;-(carbomethoxy)-4-aza-5&agr;-androstan-3-one which includes the stages of: (1) dehydrogenating said starting material to produce the corresponding compo
Gormley Glenn J.
Stoner Elizabeth
Fitch Catherine D.
Goldberg Jerome D.
Merck & Co. , Inc.
Quagliato Carol S.
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