TREA

Method of treating prostatic adenocarcinoma

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Information

  • Patent Grant
  • 5300294
  • Patent Number
    5,300,294
  • Date Filed
    Wednesday, June 27, 1990
    34 years ago
  • Date Issued
    Tuesday, April 5, 1994
    30 years ago
Information
Abstract
Invented is a Method of Treating Prostatic Adenocarcinoma by employing a steroid 5-.alpha.-reductase inhibiting compound or a combination of steroid 5-.alpha.-reductase inhibiting compounds.
Description

This invention relates to a method of treating prostatic adenocarcinoma by employing a steroid 5-.alpha.-reductase inhibiting compound. Advantageously the method of this invention employs 17.beta.-(N-t-butylcarboxamide)-androst-3,5--diene-3--carboxylic acid in the symptomatic relief of prostatic adenocarcinoma.
BACKGROUND OF THE INVENTION
The class of steroidal horomones known as androgens is responsible for the physical characteristics that differentiate males from females. Of the several organs that produce androgens, the testes produce these hormones in the greatest amounts. Centers in the brain exert primary control over the level of androgen production. Numerous physical manifestations and disease states result when ineffective production control results in excessive androgen hormone production. For example, acne vulgaris, seborrhea, female hirsutism, and benign prostatic hypertrophy are correlated with elevated androgen levels. Additionally, the incidence of male pattern baldness has been associated with high androgen levels.
Testosterone is the principal androgen secreted by the testes and is the primary androgenic steroid in the plasma of males. It now is known that 5-.alpha.-reduced androgens are active hormones in some tissues such as the prostate and sebaceous gland. Circulating testosterone thus serves as a prohormone for dihydrotestosterone (DHT), its 5-.alpha.-reduced analogue in these tissues but not in others such as muscle and testis. Steroid 5-.alpha.-reductase is a NADPH dependent enzyme that converts testosterone to DHT. The importance of this enzyme in male development was dramatically underscored by discovery of a genetic steroid 5-.alpha.-reductase deficiency in male pseudohermaphrodites. Imperato-McGinley, J., et al., (1979), J. Steroid Biochem. 11:637 648.
Recognition of the importance of elevated DHT levels in various disease states has stimulated many efforts to synthesize inhibitors of this enzyme.
The first inhibitor described was 4-androsten-3-one-17.beta.-carboxylic acid by Hisa and Voight in 1973 J. Invest. Dermat. 62:224-227. (4R)-5,10-seco-19-norpregna-4,5-diene-3,10,20-triane was the next inhibitor to be described and also has found utiltiy as an affinity label for 5-.alpha.-reductase. Robaire, B., et al., (1977), J. Steroid Biochem. 8:307-310. (5.alpha.,20-R)-4-diazo-21 -hydroxy-20-methlypregnan-3-one has been reported as a potent, time dependent inhibitor of steroid 5-.alpha.-reductase. Blohm, T. R., et al., (1980), Biochem. Biophys. Res. Comm. 95:273-280; U.S. Pat. No. 4,317,817, Mar. 2, 1982. 17.beta.-N,N-diethylcarbomoyl-4-methyl-4-aza-5-.alpha.-androstan-3-one is exemplary of a group of 4-aza steroid inhibitors of steroid 5-.alpha.-reductase described in U.S. Pat. No. 4,377,584 which issued Mar. 22, 1983, and in Liang, T., et al., (1983), J. Steroid Biochem. 19, 385-390. 17.alpha.-acetoxy-6-methylenepregn-4-ene-3,20-dione also has been shown to be a time-dependent inactivator of steroid 5-.alpha.-reductase. Petrow, V., et al., (1981), Steroids 38:121-140.
Other steroid 5-.alpha.-reductase inhibitors also have been described. U.S. Pat. No. 4,361,578 which issued Jun. 2, 1986, describes a class of homosteroid enzyme inhibitors. U.S. Pat. No. 4,191,759 discloses amides of 17.beta.-carboxy-4-androsten-3-one that are active as steroid 5-.alpha.-reductase inhibitors. Japanese Patents J60146855-A and J60116657-A disclose various aniline derivatives having numerous activities including 5-.alpha.-reductase inhibiting activity. Japanese Patent 60142941-A discloses phenyl-substituted ketones having 5-.alpha.-reductase inhibiting activity and European Patent EP173516-A discloses various phenyl substituted amides having similar activity. Shiseido referenced terpene derivatives that are active inhibitors of steroid 5-.alpha.-reductase. Japanese Patent J59053417-A.
It has been postulated but never proven that the inhibition of steroid 5-.alpha.-reductase would result in a therapeutic effect on prostatic adenocarcinoma in mammals, Novel Approaches to Cancer Chemoterapy, Pub: Academic Press, Inc. (1984) Ch.8 V. Petrow and G. Padilla 5-.alpha.-reductase: A target enzyme for Prostatic Cancer, however, contrary evidence has also been published, Liang, t., et al., (1985), Endocrinology 117, No. 2: 571-579.
It has now been discovered that steroid 5-.alpha.-reductase inhibitors do have a therapeutic effect on prostatic adenocarcinoma of mammals.
SUMMARY OF THE INVENTION
The present invention resides in the discovery that steroid 5-.alpha.-reductase inhibiting compounds have a therapeutic effect on prostatic adenocarcinoma.
Included in the present invention are combinations of steriod 5-.alpha.-reductase inhibitors and pharmaceutical compositions comprising a pharmaceutical carrier and a compound or a combination of compounds useful in the method of the invention.
DESCRIPTION OF THE INVENTION
An inhibitor of steriod 5-.alpha.-reductase or a combination of inhibitors of steroid 5-.alpha.-reductase are used in a pharmaceutical composition to treat prostatic adenocarcinoma.
Also included are derivatives of these compounds which may either give rise to the parent compounds in vivo or be useful themselves, such as pharmaceutically acceptable addition salts. Salts of these compounds containing a basic group are formed with organic or inorganic acids in the presence of a basic compound by methods known to the art. For example, the compound is reacted with an inorganic or organic acid in an aqueous miscible solvent such as ethanol with isolation of the salt by removing the solvent or in an aqueous immiscible solvent when the acid is soluble therein, such as ethyl ether or chloroform, with the desired salt separating directly or isolated by removing the solvent. Examplary of the acid addition salts which are included in this invention are maleate, fumarate, lactate, oxalate, methane sulfonate, ethanesulfonate, benzenesulfonate, tartrate, citrate, hydrochloride, hydrobromide, sulfate, phosphate and nitrate salts. Pharmaceutically acceptable base addition salts of compounds of the invention containing an acidic group are prepared by known methods from organic and inorganic bases include nontoxic alkali metal and alkaline earth bases, for example, calcium, sodium, and potassium hydroxide; ammonium hydroxide, and nontoxic organic bases such as triethylamine, butylamine, piperazine, and (trihydroxymethly)methylamine. Prodrug derivatives include O-esters, especially the tri-O-lower alkanoly ester having from 2-8-carbon atoms in each alkanoyl group; O-methly ethers or sulfate esters. Separated R and S stereoisomers are also useful.
Compounds that are considered to be steroid 5-.alpha.-reductase inhibitors include:
17.beta.-(N-t-butylcarboxamide)-5-.alpha.-androst-1-ene-4-aza-3-one,
(2OR)-hydroxymethyl-4-methyl-4-aza-5-alphapregnane-3-one,
17.beta.-(N,N-diisopropylcarboxamide)-5-.alpha.-8(14)androsten-4-methyl-4-aza-3-one,
17.beta.-(N-t-butylcarboxamide)-5-.alpha.-8(14)-androsten-4-methyl-4-aza-3-one,
17.beta.-(N,N-diisopropylcarboxamide)-3-nitro-5-.alpha.-androst-3-ene,
17.beta.-(N-t-butylcarboxamide)-3-nitro-5-.alpha.-androst-3-ene,
17.beta.-(N,N diisopropylcarboxamide)-3-nitro-5-.alpha.-androst-2-ene,
17.beta.-(N-t-butylcarboxamide)-androst-3,5-diene-3-carboxylic acid or a salt thereof,
17.beta.-(N,N-diisopropylcarboxamide) androst-3,5-diene-3-carboxylic acid or a salt thereof,
17.beta.-(N,N-diisopropylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylic acid or a salt thereof.
17.beta.-(N-t-butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylic acid or a salt thereof,
17.beta.-(N,N-diisopropylcarboxamide)-estra-1,3,5(10)-triene-3-sulfonic acid or a salt thereof,
20-.alpha.-(hydroxymethyl)-A-nor-5-.alpha.-pregn-1-ene-2-carboxylic acid or a salt thereof,
17.beta.-(N-t-butylcarboxamide)-estra-1,3,5(10)-triene-3-sulfonic acid or a salt thereof,
17.beta.-(N,N-diisopropylcarboxamide)estra-1,3,5(10)-triene-3-phosphonic acid or a salt thereof,
17.beta.-(N-t-butylcarboxamide)-estra-1,3,5(10)-triene-3-phosphonic acid or a salt thereof,
17.beta.-(N,N-diisopropylcarboxamide)estra-1,3,5(10)-triene-3-phosphinic acid or a salt thereof,
17.beta.-(N-t-butylcarboxamide)-estra-1,3,5(10)-triene-3-phosphinic acid or a salt thereof,
17.beta.-(N-t-butylcarboxamide)-androst-3,5-diene-3-phosphinic acid or a salt thereof,
17.beta.-(N,N-diisopropylcarboxamide)-androst-3,5-diene-3-phosphinic acid or a salt thereof,
17.beta.-(N-t-butylcarboxamide)-androst-3,5-diene-3-phosphonic acid or a salt thereof,
17.beta.-(N,N-diisopropylcarboxamide)-androst-3,5-diene-3-phosphonic acid or a salt thereof,
(E)-17.beta.-(N,N-diisopropylcarboxamide)-androst-4-ene-3-ylidene-acetic acid,
17.beta.-(N,N-diisopropylcarboxamide)-androst-3,5-diene-3-acetic acid,
(Z)-17.beta.-(N,N-diisopropylcarboxamide)-androst-4-ene-3-ylidene-acetic acid,
17.beta.-(N,N-diisopropylcarboxamide)-5.alpha.-androst-2-ene-3-acetic acid,
(Z)-17.beta.-(N,N-diisopropylcarboxamide)-5.alpha.-androst-3-ylidene-acetic acid,
17.beta.-(N,N-diisopropylcarboxamide)-5.alpha.-androst-3-ene-3-acetic acid, and
17.beta.-(N-t-butylcarboxamide)-5.alpha.-androst-2-ene-3-acetic acid.
Persons skilled in the art can readily determine if a compound is a steriod 5-.alpha.-reductase inhibitor by known methods. All such compounds are included within the scope of this invention.
Because steroid 5-.alpha.-reductase inhibitors decrease the size of prostate tumors, they have therapeutic utility in treating prostate adenocarcinoma.
17.beta.-(N-t-butylcarboxamide)-androst-3,5-diene-3-carboxylic acid (compound A) was tested for its in vivo potency in treating human prostatic cancer.
To perform experiments on the human prostatic cancer model, a total of 80 nude mice were used. Each of these animals was inoculated in the flank with PC 82 human prostatic cancer and allowed to go untreated until the tumors were approx. 0.5 cc.sup.3 in size (approx. 50 days after inoculation). After this period, 60 of the 80 animals were castrated. A 1 cm long tertosterone filled silastic capsule was implanted subcutaneously in the flank of 20 of the castrated animals and a 2 cm long dihydrotestosterone filled silastic capsule was implanted subcutaneously in the flank of 20 of the castrated animals. The 80 animals were set up in 8 groups as follows:
GROUP 1--intact rats fed twice a day with vehicle alone (intact controls).
GROUP 2--castrated rats fed twice a day with vehicle and not implanted with testosterone or dihydrotestosterone capsule (castrate controls).
GROUP 3--intact rats fed compound (A) (BID) 50 mg/kg.
GROUP 4--castrated rats fed compound (A) (BID) 50 mg/kg and not implanted with testosterone or dihydrotestosterone capsule.
GROUP 5--castrated rats fed twice a day with vehicle and implanted with testosterone capsule.
GROUP 6--castrated rats fed compound (A) (BID) 50 mg/kg and implanted with testosterone capsule.
GROUP 7--castrated rats fed twice a day with vehicle and implanted with dihydrotesterone capsule.
GROUP 8--castrated rats fed compound (A) (BID) 50 mg/kg and implanted with dihydrotestosterone capsule.
The animals were administered the 5-.alpha.-reductase inhibiting compound twice a day (BID) for 5 consecutive weeks. The test compound was dissolved in propylene glycol and diluted in water. Tumor volume was measured by caliper twice a week, At the end of the treatment period blood was collected from the animals and they were sacrificed, the ventral prostrates were excised and weighed and the serum androgen levels were determined by known methods. Ewing at al Endrocrinoloqy 113:2004 2009, 1983.
The nude mice treated with compound (A) realized a significant decrease in the size of the implanted PC-82 human prostatic cancer, in addition to other therapeutic effects normally associated with inhibitors of steriod 5-.alpha.-reductase. Thus, the administration of a steroid 5-.alpha.-reductase inhibiting compound results in a therapeutic effect on human prostatic adenocarcinoma.
The claimed compounds and combinations are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are employed. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olice oil, saline, and water. Similarly, the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, along or with a wax. The amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
The pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.
Doses of the present compounds and combinations in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity selected from the range of 0.1-1000 mg/kg of each active compound, preferably 1-100 mg/kg. The selected dose is administered to a human patient in need of treatment for prostatic adenocarcinoma from 1-6 times daily, orally, by injection or continuously by infusion. Oral dosage units for human administration preferably contain from 1 to 500 mg of active compound. Oral administration, which uses lower dosages is preferred. Parenteral administration, at higher dosages, however, also can be used when safe and convenient for the patient.
The method of this invention of treating prostatic adenocarcinoma comprises administering to a subject in need thereof an effective amount of a steroid 5-.alpha.-reductase inhibiting compound.
Following are the results of testing the compounds of this invention:
TABLE I
The effect of 17.beta.-(N-t-butylcarboxamide)-androst-3,5-diene-3-carboxylic acid (compound A) on inhibiting the growth of PC-82 Human Prostatic adenocarcinoma.
TABLE I__________________________________________________________________________Treatment Tumor volume (cm.sup.3) at identical weeks of treatmentGroup No. (N = 6 rats/group) 0 1 2 3 4 5__________________________________________________________________________Group 1 Non-intact 0.59 .+-. 0.06 0.71 .+-. 0.24 0.87 .+-. 0.19 1.18 .+-. 0.20 1.28 .+-. 0.18 1.55 .+-. 0.31 Control (100).sup.b (120) (147) (200) (217) (263)Group 2 Castrated 0.64 .+-. 0.07 0.56 .+-. 0.11 0.44 .+-. 0.09 0.42 .+-. 0.15 0.25 .+-. 0.16 0.27 .+-. 0.10 (100) (88) (69) (66) (39) (42)Group 3 Intact + 0.50 .+-. 0.04 0.45 .+-. 0.05* 0.40 .+-. 0.04* 0.38 .+-. 0.07* 0.36 .+-. 0.03* 0.34 .+-. 0.06* compound A (100) (90) (80) (76) (72) (68)Group 4 Castrated + 0.62 .+-. 0.10 0.51 .+-. 0.11 0.35 .+-. 0.09 0.30 .+-. 0.10 0.28 .+-. 0.07 0.29 .+-. 0.05 compound A (100) (82) (56) (48) (45) (47)Group 5 Castrated + 0.48 .+-. 0.12 0.69 .+-. 0.07 0.78 .+-. 0.14 1.12 .+-. 0.15 1.32 .+-. 0.19 1.60 .+-. 0.43 testosterone (106) (143) (162) (233) (275) (333) implantGroup 6 Castrated + 0.55 .+-. 0.17 0.52 .+-. 0.10 0.45 .+-. 0.09 0.40 .+-. 0.11 0.35 .+-. 0.17 0.38 .+-. 0.13 testosterone (100) (95) (82) (73) (64) (69) implant + compound AGroup 7 Castrated + 0.62 .+-. 0.10 0.74 .+-. 0.07 0.93 .+-. 0.12 1.24 .+-. 0.22 1.42 .+-. 0.31 1.78 .+-. 0.32 DHT implant (100) (119) (150) (200) (229) (287)Group 8 Castrated + 0.49 .+-. 0.09 0.65 .+-. 0.11 0.87 .+-. 0.13 1.05 .+-. 0.19 1.32 .+-. 0.35 1.72 .+-. 0.28 DHT implant + (100) (133) (177) (214) (269) (351) compound A__________________________________________________________________________ *Statistically significant .sup.b Values in parentheses are the relative percentages versus the starting values for each group at time 0.
The data in the above table demonstrates the therapeutic effect of steroid 5-.alpha.-reductase inhibitors on human prostatic adenocaroinoma.





The following examples illustrate preparation of the claimed pharmaceutical compositions containing steroid 5-.alpha.-reductase inhibitors. The examples are not intended to limit the scope of the invention as defined herein above and as claimed below.
EXAMPLE 1
An oral dosage form for administering the claimed compounds is produced by screening, mixing and filling into hard gelatin capsules the ingredients in the proportions shown in table II below.
TABLE II______________________________________INGREDIENTS AMOUNTS______________________________________17.beta.-(N-t-butylcarboxamide)- 100 mgandrost-3,5-diene-3-carboxylicacidMagnesium stearate 5 mgLactose 75 mg______________________________________
EXAMPLE II
The sucrose, calcium sulfate dihydrate and claimed compound shown in Table II below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.
TABLE III______________________________________INGREDIENTS AMOUNTS______________________________________17.beta.-(N-t-butylcarboxamide)- 100 mgandrost-3,5-diene-3-carboxylicacidCalcium sulfate dihydrate 150 mgSucrose 20 mgStarch 10 mgTalc 5 mgStearic Acid 3 mg______________________________________
EXAMPLE III
17.beta.-(N-t-butylcarboxamide)-androst-3,5-diene-3-carboxylic acid (1.0 g) is dissolved in 20 g of soybean oil and emulsified by mixing with 1.2 g of egg phospholipid and enough water to bring the final volume to 100 ml. The formed interlipid formulation is suitable for intravenous administration.
While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming with the scope of the following claims is reserved.
Claims
  • 1. A method of treating human prostatic adenocarcinoma which comprises administering orally, by injection or infusion to a subject in need thereof a dosage unit of from about 0.1 mg/kg to about 1000 mg/kg of a steroid 5-.alpha.-reductase inhibiting compound from one to six times daily.
  • 2. The method of claim 1 which comprises administering a dosage unit containing from about 1 mg/kg to about 100 mg/kg of said steroid 5-.alpha.-reductase inhibiting compound.
  • 3. The method of claim 1 in which the steroid 5-.alpha.-reductase inhibiting compound is 17.beta.-(N-t-butylcarboxamide)-androst-3,5-diene-3-carboxylic acid or a salt thereof.
  • 4. The method of claim 1 in which the steroid 5-.alpha.-reductase inhibiting compound is:
  • 17.beta.-(N-t-butylcarboxamide)-5-.alpha.-androst-1-ene-4-aza-3-one,
  • 17.beta.-(N,N-diisopropylcarboxamide)-3-nitro-5-.alpha.-androst-3-ene,
  • 17.beta.-(N-t-butylcarboxamide-3-nitro-5-.alpha.-androst-3-ene,
  • 17.beta.-(N,N-diisopropylcarboxamide)-3-nitro-5-.alpha.-androst-2-ene,
  • 17.beta.-(N-t-butylcarboxamide)-androst-3,5-diene-3-carboxylic acid or a salt thereof,
  • 1.beta. -(N,N-diisopropylcarboxamide)-androst-3,5-diene-3-carboxylic acid or a salt thereof,
  • 17.beta.-(N,N-diisopropylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylic acid or a salt thereof,
  • 17.beta.-(N-t butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylic acid or a salt thereof,
  • 17.beta.-(N,N-diisopropylcarboxamide)-estra-1,3,5(10)-triene-3-sulfonic acid or a salt thereof,
  • 20-.alpha.-(hydroxymethyl)-A-nor-5-.alpha.-pregn-1-ene-2-carboxylic acid or a salt thereof,
  • 17.beta.-(N-t-butylcarboxamide)-estra-1,3,5(10)-triene-3-sulfonic acid or a salt thereof,
  • 17.beta.-(N,N-diisopropylcarboxamide)estra-1,3,5(10)-triene-3-phosphonic acid or a salt thereof,
  • 17.beta.-(N-t-butylcarboxamide)-estra-1,3,5(10)-triene-3-phosphonic acid or a salt thereof,
  • 17.beta.-(N,N-diisopropylcarboxamide)estra-1,3,5(10)-triene-3-phosphinic acid or a salt thereof,
  • 17.beta.-(N-t-butylcarboxamide)-estra-1,3,5(10)-triene-3-phosphinic acid or a salt thereof,
  • 17.beta.-(N-t-butylcarboxamide)-androst-3,5-diene-3-phosphinic acid or a salt thereof,
  • 17.beta.-(N,N-diisopropylcarboxamide)-androst-3,5-diene-3-phosphinic acid or a salt thereof,
  • 17.beta.-(N-t-butylcarboxamide)-androst-3,5-diene-3-phosphonic acid or a salt thereof,
  • 17.beta.-(N,N-diisopropylcarboxamide)-androst-3,5-diene-3-phosphonic acid or a salt thereof,
  • (E)-17.beta.-(N,N-diisopropylcarboxamide)-androst-4-ene-3-ylidene acetic acid,
  • 17.beta.-(N,N-diisopropylcarboxamide)-androst-3,5-diene-3-acetic acid,
  • (Z)-17.beta.-(N,N-diisopropylcarboxamide)-androst-4-ene-3-ylidene-acetic acid,
  • 17.beta.-(N,N-diisopropylcarboxamide)-5.alpha.-androst-2-ene-3-acetic acid,
  • (Z)-17.beta.-(N,N-diisopropylcarboxamide)-5.alpha.-androst-3-ylidene-acetic acid,
  • 1.beta. -(N,N-diisopropylcarboxamide)-5.alpha.-androst-3-ene-3-acetic acid or
  • 17.beta.-(N-t-butylcarboxamide)-5.alpha.-androst-2-ene-3-acetic acid.
  • 5. The method of claim 1 in which the steroid 5-.alpha.-reductase inhibiting compound is 17.beta.-(N-t-butylcarboxamide)-5.alpha.-androst-1-ene-4-aza-3-one.
  • 6. The method of claim 1 in which the steroid 5-.alpha.-reductase inhibiting compound is 17.beta.-(N-t-butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylic acid or a salt thereof.
  • 7. A method of treating human prostatic adenocarcinoma which comprises administering orally, by injection of infusion to a subject in need thereof a dosage unit of from about 0.1 mg/kg to about 1000 mg/kg of each active compound of a combination of compounds of claim 4.
  • 8. The method of claim 1 in which the compound is administered orally.
  • 9. The method of claim 1 in which the compound is administered by injection.
  • 10. The method of claim 1 in which the compound is administered by infusion.
  • 11. The method of claim 1 which comprises administering a dosage unit containing from about 1 mg to about 500 mg of said steroid 5-.alpha.-reductase inhibiting compound.
  • 12. The method of claim 2 in which the steroid 5-.alpha.-reductase inhibiting compound is 17.beta.-(N-t-butylcarboxamide)-5-.alpha.-androst-1-ene-4-aza-3-one.
  • 13. The method of claim 8 in which the steroid 5-.alpha.-reductase inhibiting compound is 17.beta.-(N-t-butylcarboxamide)-androst-3,5-diene-3-carboxylic acid or a salt thereof.
  • 14. The method of claim 8 in which the steroid 5-.alpha.-reductase inhibiting compound is 17.beta.-(N-t-butylcarboxamide)-5-.alpha.-androst-1-ene-4-aza-3-one.
  • 15. The method of claim 8 in which the steroid 5-.alpha.-reductase inhibiting compound is 17.beta.-(N-t-butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylic acid or a salt thereof.
  • 16. The method of claim 2 in which the steroid 5-.alpha.-reductase inhibiting compound is 17.beta.-(N-t-butylcarboxamide)-androst-3,5-diene-3-carboxylic acid or a salt thereof.
  • 17. The method of claim 2 in which the steroid 5-.alpha.-reductase inhibiting compound is 17.beta.-(N-t-butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylic acid or a salt thereof.
  • 18. The method of claim 11 in which the steroid 5-.alpha.-reductase inhibiting compound is 17.beta.-(N-t-butylcarboxamide)-5-.alpha.-androst-1-ene-4-aza-3-one.
  • 19. The method of claim 11 in which the steroid 5-.alpha.-reductase inhibiting compound is 17.beta.-(N-t-butylcarboxamide)-androst-3,5-diene-3-carboxylic acid.
  • 20. The method of claim 11 in which the steroid 5-.alpha.-reductase inhibiting compound is 17.beta.-(N-t-butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylic acid.
US Referenced Citations (9)
Number Name Date Kind
4882319 Holt et al. Nov 1989
4910226 Holt et al. Mar 1990
4937237 Holt et al. Jun 1990
4946834 Holt et al. Aug 1990
4970205 Holt et al. Nov 1990
5017568 Holt et al. May 1991
5032586 Metcalf et al. Jul 1991
5041433 Holt et al. Aug 1991
5137882 Holt et al. Aug 1992
Foreign Referenced Citations (7)
Number Date Country
0004949B1 Apr 1978 EPX
200859 Nov 1986 EPX
279010 Aug 1988 EPX
0285383A2 Oct 1988 EPX
414490A Feb 1991 EPX
414491A Feb 1991 EPX
9100733 Jan 1991 WOX
Non-Patent Literature Citations (11)
Entry
"Retardation of Prostate Tumor Progression in the Noble Rat by 4-Methyl-4-Aza-Steroidal Inhibitors of 5 Alpha-Reductase", Kadohama et al; J. Natl. Cancer Inst; 74(2):475-86 1985 ISSN 0027-8874.
Gormley, The Urologic Clinics of North America vol. 18; No. 1, pp. 93-98 (1991).
Sandberg, et al. Progress in Cancer Research Therapy vol. 31; No. 2, pp. 477-489 (1984).
Holt et al, J. Med. Chem. vol. 33; No. 3, pp. 937-942 (1990), pp. 943-950.
Holt et al, Med. Chem. vol. 33; No. 3, pp. 943-950 (1990).
Levy et al., J. Steroid Biochem. vol. 34; Nos. 1-6, pp. 571-575 (1989).
The Prostate 18:215-227, (1991); Brooks, et al.
J. Steroid Biochem (24), 1986, 887-86; Cooke, et al.
Bio Chemistry (28), 1989, Brandt, et al.
Liang et al., Endocrinology, 117 No. 2, 571-579 (1985).
Petrow et al., Novel Approaches to Cancer Chemotherapy, pub: Academic Press, Inc., CH.8.V 269-304 (1984).