METHOD OF TREATMENT OF ANDROGEN-RELATED DISEASES

Abstract: A method of treatment of androgen-related diseases such as prostate cancer in susceptible male animals, including humans, comprises administering novel antiandrogens and/or novel sex steroid biosynthesis inhibitors as part of a combination therapy. Sex steroid biosynthesis inhibitors, especially those capable of inhibiting conversion of dehydroepiandrosterone (DHEA) or 4-androstenedione ( DELTA <4>-dione) to natural sex steroida (and testosterone into dihydrotestosterone) in peripheral tissues, are used in combination with antiandrogens usually after blockade of testicular hormonal secretions. Antiestrogens can also be part of the combination therapy. Pharmaceutical compositions and two, three, four and five component kits are useful for such combination treatment.

Description: METHOD OF TBKATHEHT OF AHDROGEH-RELAIED DISEASES BΔCB3SOUHD OF THE MVEHTIQH This invention relates to a method of treatment of androgen-related diseases such as prostate cancer in warm-blooded male animals (including humans) in need of such treatment, and in particular, to a combination therapy comprising administering an antiandrogen in association with an inhibitor of sex steroid biosynthesis to such animals. The invention also includes pharmaceutical compositions and kits useful for such treatment. Androgen-dependent diseases include diseases whose onset, maintenance or progress is, at least in part, dependent upon biological activities indu¬ ced by androgens (e.q. testosterone and dihydrotestosterone) . In one embodiment, the invention provides a treatment of hormone-dependent pros¬ tate cancer in warm-blooded male animals which comprises administering both an antiandrogen and at least one inhibitor of sex steroid biosynthe¬ sis capable of inhibiting conversion of dehydroepiandrosterone or 4-an- drostenedione to natural sex steroids in extra-testicular and extra-adre¬ nal tissues. While various investigators have been studying hormone-dependent prostate cancer, none have proposed the combination therapy of this invention. A.V. Schally et al.. Cancer Treatment Reports, 68 (No. 1) 281-289 (1984) , suasπarize the results of animal and clinical studies on growth inhibition of hormone-dependent mammary and prostate tumors by use of analogues of luteinizing hormone-releasing hormones, the so-called LHRH agonists and suggest that LHRH analogs and/or antagonists may have poten¬ tial for treating breast cancer. T.ff. Redding and A.V. Schally, Proc. Natl Acad. Sci. UA 80, 1459- 1462 (1983), relates to inhibition of prostate tumor growth in rats by chronic use of an LHRH agonist, [D-Trp*jLHRH. U.S. Patent Number 4,329,364 relates to use of the antiandrogen, 4'- nitro-3'trifluoromethyl isobutyranilide for treatment of prostatic cancer. U.S. Patent Number 4,472,382 relates to treatment of prostate adeno- carcino a, benign prostate hypertrophy and hcraone-dependent mammary tumors may with various LHRH agonists and treatment of prostate adenocar- cinoma and benign hypertrophy by use of various LHRH agonists and an antiandrogen. U.S. Patent Number 4,659,695 (Labrie) relates to treatment of prostate cancer in animals whose testicular hormonal secretions are blocked. The method of treatment includes administering an antiandrogen such as flutamide as an inhibitor of sex steroid biosynthesis such as aminoglttethimide and/or ketoconazole. Some clinical improvement in men with prostate cancer by use of the two 'LHRH agonists, Buserelin and Leuprolide, is also reported by N. Faure et ai. at pages 337-350 and by R.J. Santen et al. at oaees 351-364. res- pectively, LHRH and its Analogues - A new Class of Contraceptive and the¬ rapeutic Agents (B.H. Vickery and J.J. Nestor, Jr., and E.S.E. Hafez, eds), Lancaster, MTP Press, (1984). R. Santen et al.. The Journal of Steroid Biochemistry, volume 20, no 6B, at page 1375 (1984), relates that the use of ketoconazole in combina¬ tion with chronic administration of Leuprolide in rodents decreased basal and Leuprolide-stimulated testosterone levels. One of Applicant's Co-pending U.S. Patent Applications Serial Number 07/321,926 filed March 10, 1989, relates to a combination therapy for treatment of estrogen-related diseases by inhibiting ovarian hormonal secretions and administering an antiestrogen in combination with at least one of several enumerated activity blockers, sex steroid formation inhi¬ bitors and the like. D. erle et al., The Journal of Steroid Biochemistry, volume 20, no. 6B, at page 1395 (1984) relates to the combined use of a LHRH analogue and ketoconazole producing objective responses in some prostate cancer patients who have relapsed or failed to respond to treatment with a LHRH analogue alone. F. Labrie et al., The Prostate, 4, 579-594 (1983), disclose that use of a combination therapy of an LHRH agonist (Buserelin) and an antiandro¬ gen (Anandron) to treat advanced prostate cancer in previously untreated patients effects simultaneous elimination of androgens of both testicular and adrenal origin. F. Labrie et al., J. Steroid Biochem. , 19, 999-1007 (1983), disclose the treatment of prostate cancer by the combined administration of an LHRH agonist and an antiandrogen. Labrie et al. disclose animal and cli¬ nical data in support of the proposition that the combined LHRH/antian- drogen treatment neutralizes the stimulatory influence of all androgens on the development and growth of androgen-dependent prostatic cancer. F. Labrie et al. , Abstracts of the 7th International Congress of Endocrinology, Excerpta Hedica (1984) at page 98 disclose that treatment of prosrate cancer patients with LHRH agonists alone causes a transient increase in serum androgen levels lasting for 5 to 15 days before castra¬ tion levels are reached. While F. Labrie et al. recommend that orchiec- to y, estrogen and LHRH agonists alone should not be further used for treatment of prostate cancer in the absence of a pure antiandrogen, there still is a need for a method of treatment of prostate cancer that effects more complete androgen blockage at the start as well as during the full period of treatment. There are many data indicating that estrogens have a stimulatory effect on prostatic growth (Lee et al., 1981; J. Androl. 2: 293-299; Belis et al., 1983; J. Androl. 4; 144-149; Walsh and Wilson, 1976; J. Clin. Invest. 57: 1093-1097; De Klerk et al., 1985; Prostate 7, 1-12; Habesucht et al., 1987; Prostate 11: 313-326). Estrogens have also been found to enhance the growth-promoting effect of- androgens (Farnsworth, 1969; Invest. Urol. 6: 423-427; Groom et al., 1971; Biochem. J. 122: 125-126; Lee et ai., 1973; Steroids 22: 677-683). Estrogen receptors have been demonstrated in human normal, hyper- plastic and cancer prostatic tissue (Hobbs et al., 1989; Proc. 84th Endocrine Soc, Meeting, abst. No. 1410; Hobbs et al., 1983; J. Steroid Biochem. 19, 1279-1290; Wagner et al., 1975; Acta Endocrinol. (Kbh) , suppl. 193, 52; and also in laboratory animal prostatic tissue (Swaneck et al., 1982; Biochem. Biophys. Res. Coπππun. 106: 1441-1447). Horeover, androgen receptor levels were found to be elevated in prostatic tissue of patients treated with estrogen, thus indicating a stimulatory effect of estrogen on the level of androgen receptors in prostatic tissue (Hobbs et al., 1983; J. Ster. Biochem. 19, 1279-1290). A similar stimulatory effect of estrogen has been observed in the dog prostate (Hoore et al., 1979; J. Clin. Invest. 63, 351-357). In the prostate as well as in many other tissues, testosterone is irreversibly converted by 5o-reductase into the more potent androgen di¬ hydrotestosterone (Bruchovsky and Wilson, J. Biol. Chem. 243: 2012-2021, 1968; Wilson, Handbook of Physiology 5 (section 7), pp. 491-508, 1975). Inhibitors of 5α-reductase have been found to inhibit prostatic growth (Brooks et al., Endocrinology 109: 830, 1981; Brooks et al., Proc. Soc Exp. Biol. Hed. 169: 67, 1982; Brooks et al., Prostate 3: 35, 1982; Wenderoth et al., Endocrinology 113, 569-573, 1983; HcConnell et al., J. Urol. 141: 239A, 1989); Stoner, E., Lecture on the role of 5o-reductase inhibitor in benign prostatic hypertrophy, 84th AUA Annual Meeting, Dallas, May 8th, 1989. The inhibitory effect of the 5α-reductase inhibitor Merck L. 652,931 on prostatic and seminal vesicle development in the prepubertal rat was described in Proc. 71st Annual Meeting of Endocrine Society, abst. #1165, p. 314, 1989. The inhibitory effect of MK-906 on dihydrotestosterone formation in men has been described in men by Gormley et al., in Proc. 71st Annual Meeting of Endocrine Society, abst. #1225, p.- 329, -1989; Imperato-McGiniey et al., in Proc. 71st Annual Meeting of Endocrine Society, abst. #1639, p. 432, 1989; G-aller and Franson, in Proc. 71st Annual Meeting of Endocr. Soc, abst. #1640, p. 432, 1989, and Tenover et al., in Proc 71st Annual Meeting of Endocr. Soc, abst. #583, p. 169, 1989. The activity of the 5α-reductase inhibitors N,N-diethyl-4-πtethyl-3- oxo-4-aza-5α-androstane-17β-carboxa_tnide (4-MA) and 6-methylene-4-preg- nene-3,20-dione (LY207320) has been described by Toomey et al., Proc. 71st Annual Heeting of Endocr. Soc, abst. #1226, p. 329, 1989. SUMMARY OF THE IHVENTION It is an object of the present invention to provide combination the¬ rapy for the treatment of prostate cancer wherein the treatment selecti¬ vely inhibits the formation and/or action of hormones which would other¬ wise contribute to tumor growth. It is another object of the invention to provide combination therapy having increased effectiveness in slowing or reversing tumor growth. It is another object of the invention to provide therapy for treat¬ ing prostate cancer having significantly reduced frequency of unwanted side effects. It is a further object of the invention to provide kits having a plurality of active ingredients (with or without diluent or carrier) which, together, may be effectively utilized for carrying out the novel combination therapies of the invention. It is another object of the invention to provide a novel pharmaceu¬ tical composition which is effective, in and of itself, for utilization in a beneficial combination therapy because it includes a plurality of active ingredients which may be utilized in accordance with the inven¬ tion. In one aspect, the present invention provides a method for treating prostate cancer in humans or other warm-blooded animals in need of such treatment, said method comprising the steps of blocking androgen recep¬ tors by administering a therapeutically effective amount of an antiandro¬ gen having as part of its molecular structure a substituted or unsubstituted androgenic nucleus of the formula: said antiandrogen having as another part of its molecular structure at least one side chain represented by the formula: -R 1 [-B-R 1 -] L-G wherein said side chain is substituted onto said androgenic nucleus at a position selected from the group consisting of 6α, 7α, 14α, 15α, 16 , 17α and 17β, and wherein: x is an integer from 0 to 6, wherein at least one of L and G is a polar moiety distanced from said ring carbon by at least three interven¬ ing atoms, and wherein: R- and R* are independently either absent or selected from the group consisting of straight- or branched-chain alkylene, straight- or branched chain alkynylene, straight- or branched—chain alkenylene, phenylene and fluoro-substituted analogs of the foregoing; B is either absent or selected from the group consisting of -0-, -S-, -Se-, -SO-, -SO,-, -_NR»-, -SiR J ,-, -CR»OR»-, -NR»CO-, -NR»CS-, -CQNR*-, -CSNR*-, -C00-, -COS-, -SCO-, -CSS-, -SCS-, -OCO- and phenylene (R* being hydrogen or lover alkyl) ; L is either a moiety which together with G, forms a heterocyclic ring having at least one nitrogen atom or is selected from the group consisting of lower alkyl, -COHR*-, -CSMR*-, -NR'CO-, -NR'CS-, -NR»C0NR»- m- -HR«C-NR*-, -S0,NR*-, -CSS-, -SCS-, -(NO)R*-, -(P0)R*-, -NR'COO-, -NR'SO,-, -0-, -NR*-, -S-, -SO- and -SO,- (R* and R 5 being independently selected from the group consisting of hydrogen and lower alkyl; and R* being selected from the group consisting of hydrogen, nitrile and nitro); and G is either a moiety which together with L forms a heterocyclic ring having at least one nitrogen atom or is selected from the group consist¬ ing of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (C 3 -C 7 )cyclo- alkyl, bromo(lower)alkyl, chloro(lower)alkyl, fluoro(lower)alkyl, cyano- (lower)alkyl, carboxy(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl, (C f -C lβ )aryl, C γ -C j ^arylal yl, di(lower)alkylamino(lower)alkyl, fluoro- substituted analogs of the foregoing, said method of treatment further comprising the step of inhibiting sex steroid formation by administering a therapeutically effective amount of at least one sex steroid formation inhibitor. In another aspect, the present invention provides a method for treatment of prostate cancer in a human or other warm-blooded animal in need of such treatment, said method comprising the steps of inhibiting r sex steroid formation by administering a therapeutically effect of amount of an inhibitor of sex steroid formation capable of blocking formation of natural sex steroids from dehydroepiandrosterone and from 4-androstene- dione in peripheral tissues (extra-adrenal and extra-testicular) , or an inhibitor of sex steroid formation having as part of its molecular structure a substituted or unsubstituted sex-steroid nucleus, and, as another part of its molecular structure at least one side chain of the formula -R 1 [-B-R*-] L-G sustituted onto a ring atom of said sex steroid nucleur wherein: x is ' an integer from 0 to 6, wherein at least one of L and G is a polar moiety distanced from said ring carbon by at least three interven¬ ing atoms, and wherein: R x and R a are independently either absent or selected from the group consisting of straight- or branched-chain alkylene, straight- or branched chain alkynylene, straight- or branched-chain alkenylene, phenylene and fluoro-substituted analogs of the foregoing; B is either absent or selected from the group consisting of -0-, -S-, -Se-, -SO-, -SO,-, -m-- , -SiR' j -, -CR'OR*-, -NR'CO-, -NR'CS-, -C0NR J -, -CSNR ϊ -, -COO-, -COS-, -SCO-, -CSS-, -SCS-, -OCO- and phenylene (R J being hydrogen or lower alkyl) ; L is either a moiety which together with G, forms a heterocyclic ring having at least cne nitrogen atom or is selected from the group consisting of lower alkyl, -CONR*-, -CSNR*-, -NR'CO-, -NR'CS-, -NR»C0NR»- NR» II -NR*C-NR*- f -SO j NR*-, -CSS-, -SCS-, -(NO)R*-, -(PO)R*-, -N «C0O-, -NR I SO J -, -0-, -NR*-, -S-, -SO- and -SO,- (R» and R s being independently selected from the group consisting of hydrogen and lower alkyl; and R* being selected from the group consisting of hydrogen, nitrile and nitro) ; and G is either a moiety which together with L forms a heterocyclic ring having at least one nitrogen atom or is selected from the group consist¬ ing of hydrogen, lover alkyl, lover alkenyl, lover alkynyl, (C,-C r )cycloalkyl, bromo(lover)al yl, chloro(lower)alkyl, fluoro(lower) alkyl, cyano(lower)alkyl, carboxy(lower)alkyl, (lower)alkoxycarboπyl (lower)alkyl, (C,-C 10 )aryl, (C j -C,,) arylalkyl, di(lover) lkylamino (lower)alkyl, fluoro-substituted analogs of the foregoing; said method of treatment further comprising administering a thera¬ peutically effective amount of an antiandrogen. In another aspect, the present invention provides a method for treating prostate cancer in a human or other warm-blooded animal in need of such treatment, said method including the steps of administering a therapeutically effective amount of an inhibitor of 5α-reductase activity and administering a therapeutically effective amount of an antiandrogen. In another aspect, the present invention provides a method for treating prostate cancer in a human or other warm-blooded animal in need of such treatment, said method including the steps of administering a therapeutically effective amount of an inhibitor of 17β-hydroxysteroid dehydrogenase and administering a therapeutically effective amount of an antiandrogen. In another aspect, the present invention provides a method for treating prostate cancer in a human or other warm-blooded animal in need of such treatment, said method including the steps of administering an effective amount of an antiandrogen and at least one sex steroid forma¬ tion inhibitor from the groups consisting of inhibitors of extragonadal and inhibitors of extraadrenal sex steroid formation. The invention also provides kits or single packages combining two or more active ingredients useful in treating prostate cancer. A kit may provide (alone or in combination vith a pharmaceutically acceptable dilu¬ ent or carrier) , an antiandrogen and at least one additional active in¬ gredient (alone or in combination with diluent or carrier) selected -from the group consisting of an LHRH agonist or LHRH antagonist, a sex steroid formation inhibitor (preferably an inhibitor of 5α-reductase activity, an inhibitor of 17β-hydroxysteroid dehydrogenase activity or an inhibitor of 3β-hydroχysteroid dehydrogenase activity) and an antiestrogen. The foregoing active ingredients may also be mixed in any of the foregoing combinations to form pharmaceutical compositions (with or with¬ out diluent or carrier) which, when administered, provide simultaneous administration of a combination of active ingredients resulting in the combination therapy of the invention. Preferably, when LHRH antagonist or agonist is used, it is administered parenterally. For this reason, it may be administered separately in instances where the other active ingre¬ dients are formulated for oral ingestion. The term "sex steroid nucleus" includes estrogenic and androgenic nuclei. As used herein, the term "androgenic nucleus" includes any compound which, in the absence of the side chain substituent specified herein (R 1 [-B-R 2 -] χ L-G) , is capable of acting as an androgen as determined by a weight increase of at least 35 percent over a seven-day period of the ventral prostate of castrated rats treated with the compound in question (15 milligrams twice daily per 100 grams of body weight) versus a control group of castrated rats. Treatment should start on the day of castration. The precise test, other than any parameters set forth in this paragraph, is that reported in Labrie et al., J. Ster. Biochem. 28, 379-384, 1987. As used herein, the term "estrogenic nucleus" includes any compound which, in the absence of the side chain substituent specified herein (R 1 [-B-R 3 -] L-G), is capable of acting as an estrogen as determined by a x weight increase of at least 100 percent over a seven-day period of the uterus of ovariectomized rats treated with the compound in question (0.5 mg twice daily per 100 grams of body weight) versus a control group of ovariectomized rats. Treatment should start on the day of castration. The precise test, other than any parameters set forth in this paragraph, is that reported in Simard et al., Hoi. Endocrinol. 2: 775-784 (1988). The following conventions apply to structural formulae set forth herein. Unless specifically designated to the contrary, substituents may have either α or β stereochemistry or, where valence permits, may repre¬ sent one substituent in α position and another in β position. Presence of optional double bonds are independent of each other. All structures include salts thereof. Atoms of any sex steroid nucleus for which no sub- stituent is shown or described may optionally be substituted or unsubsti¬ tuted so long as such substitution does not prevent the nucleus from functioning as a "sex steroid nucleus" as defined herein. Those atoms having a defined substitutent may optionally be further substituted by other substituents where their valence permits such further substitution. As used herein, the term "lower", when describing a chemical moiety means a moiety having 8 or fewer atoms. For instance, a "lover alkyl" means a C. to C, alkyl. Any moiety of more than two atoms may be straight- or branched-chain unless otherwise specified. The term "sex steroid formation inhibitor" includes both androgen and estrogen formation inhibitors and encompasses any compound which inhibits the biosynthesis of active sex steroids or their precursors. One mechanism by which sex steroid formation inhibitors act is by blocking enzymes which catalyze production of natural sex steroids (e.g. dihydro¬ testosterone), 17β-estradiol and androst-5-ene-3β-17β-diol or precursors to such sex steroids (e.g. androstenedione). Examples of such sex steroid formation inhibitors are compounds capable of blocking the enzymatic activity of, for example, 5o-reductase, β-hydroxysteroid dehydrogenase, 17β-hydroxysteroid dehydrogenase or aromatase. nτ<tττ.-Bn DESCRIPTION OF THE IWK KKKKl) EMBODIMENTS In a preferred aspect, a combination therapy for prostate cancer includes administering active ingredients effective to inhibit a variety of different mechanisms which may, directly or indirectly, lead to pros- tatic cancer growth. Desirably, the inhibition of biological activity which leads to prostatic cancer growth proceeds selectively, without substantially inhibiting other desirable biological activity. Side effects of the treatment are therefore minimized. Activation of prostatic androgen receptors stimulates growth of prostatic cancer cells. Growth may be inhibited by blocking these recep¬ tors with antiandrogens as explained herein. Growth may also be inhibited by reducing the concentration of androgens available to activate the receptors by administering at least one sex steroid synthesis inhibitor. An inhibitor of 5 -reductase catalyzes conversion of testosterone to dihydrotestosterone (DHT) . This is a particularly preferred sex steroid synthesis inhibitor because it selectively reduces DHT levels without reducing testosterone levels. DHT stimulates prostatic cancer growth to a much greater extent than does testosterone. Also absence of DHT forecloses fever desirable biological functions than does absence of testosterone. For many patients, blocking of testosterone production is also appropriate. It is believed that estrogens may also increase prostatic cancer growth. Without intending to be bound by theory, estrogens appear to at least be involved in increasing the number of androgen receptors, and may stimulate prostatic cancer growth directly by binding estrogen receptors. Regardless of the mechanism by which estrogens contribute to prostatic cancer growth, it has nov been found that a combination therapy which includes inhibition of estrogen activity can enhance effectiveness of treatment without inhibiting desirable biological functions which, in males, are largely independent of estrogen. There is shown in Figure 1 a schematic representation of the site(s) of action of various drugs, enzymes and hormones. The following abbre¬ viations are used: ER: estrogen receptor; AR: androgen receptor; DHEA: dehydroepiandrosterone; Δ s -diol: androst-5-ene-3β,17β-diol; Δ*-dione: 14 androstenedione; DHT: dihydrotestosterone; Anti-A: antiandrogen; Anti-E: antiestrogen; ARO: aromatase; 3β-HSD: 3β-hydroxysteroid dehydrogenase, Δ*-Δ* isomerase; 17β-HSD: 17β-hydroxysteroid dehydrogenase; 1: antiandro¬ gen; 2: inhibitor of 5α-reductase activity; 3: inhibitor of 17β-hydro- xysteroid dehydrogenase activity; 4: antiestrogen; 5: inhibitor of aroma¬ tase activity; 6: inhibitor of 3β-HSD activity. Referring to Figure 1, + means increase in androgen receptor levels. As may be seen from Figure 1, stimulation of the androgen receptor is shown to stimulate prostatic cancer growth, and is therefore to be prevented. In addition, stimulation of the estrogen receptor leads to increased levels of androgen receptors and thus may, in addition, exert direct stimulatory effects on prostatic cancer growth. The action of estrogens is therefore to be prevented. Blockers of sex steroid formation from DHEA and Δ*-dic in peripheral tissues does not cause inhibition of adrenal glucocort coid formation. For example, cortisol and aldosterone production is not inhibited and significant complications which could result from their inhibition are avoided. The desired inhibition of sex steroid formation is thus aimed selectively at androgens and estrogens. A method of inhibiting activation of the androgen receptor is treat¬ ment with an effective antiandrogen compound having an affinity for the receptor site such that it binds to the receptor site and prevents andro¬ gens from binding and activating the site. It is important to select antiandrogens which tend to be pure antagonists and which have no agonis¬ tic activity. Otherwise, the antiandrogen which blocks the receptor site from androgens, may itself activate the site. Preferred antiandrogens are discussed in detail below. Because it is extremely difficult to block all receptor sites, it is desirable to simultaneously decrease the concentration of .androgens available to activate androgen receptors in the prostatic cancer tissue. Hence, it is desirable to inhibit secretion of androgens by the testis. This may be accomplished by a variety of known techniques including but not limited to surgical orchiectomy or by administering LHRH agonists or antagonists. For example, LHRH analogues act in a manner effective to stop the production of bioactive luteinizing hormone, the hormone necessary to cause the testis to produce and secrete androgens and other hormones which may be converted to androgens in peri¬ pheral tissues. For some patients, it may be unnecessary to inhibit tes¬ ticular hormonal secretions where sufficiently potent antiandrogens and sex steroid biosynthesis inhibitors are administered. As may be seen from the scheme of Figure 1, a number of hormones (especially DHEA and Δ*-dione) released by the adrenals may be converted by a variety of biological pathways into androgens and estrogens in peri¬ pheral tissues. The most potent androgen produced is DHT. It is there¬ fore highly desirable to include an inhibitor of 5α-reductase which pre¬ vents the conversion of testosterone into the more potent androgen DHT. In peripheral tissues, in addition to DHT, the precursors DHEA " and Δ'-dione can be converted into the estrogens Δ'-diol and estradiol. It is desirable to have an inhibitor of 17β-hydroxysteroid dehydrogenase which prevents the formation of testosterone as well as of A s -diol and estra¬ diol. In addition, since Δ*-androstenedione can be converted into estrone and then to estradiol, it may be useful to block the activity of aromata- se, the enzyme responsible for such conversion. Other sex steroid for¬ mation inhibitors, such as inhibitors of 3β-HSD can also be used. How¬ ever, as mentioned earlier, when β-HSD is blocked in peripheral tissues, it is also likely that a similar inhibition will take place in the adre¬ nals, thus leading to low secretion of glucocorticoids and mineralocorti- coids. When such compounds are used, essential glucocorticoids and some ¬ times mineralocorticoids should be added back as part of the therapy. ■ / 6 Estrogens, at physiological concentrations, are known to stimulate the growth of the human prostatic cancer cell line LNCaP. This effect of estrogen may be inhibited however, by antiestrogenic compounds described herein. In one embodiment, the present invention provides a method of treating prostate cancer comprising the step of administering a therapeu¬ tically effective amount of an antiandrogen, and of administering a therapeutically effective amount of an inhibitor of sex steroid formation which has, as part of its molecular structure, a substituted or unsusbstituted estrogen nucleus of general structure I: wherein the dotted lines represent optional pi bonds; and wherein said compound includes as another part of its molecular structure a side chain substitution onto a ring carbon of said general structure I in at least one position selected from the group consisting of 7, 14, 15, 16, 17 (pre¬ ferably 7α, 15α, or 17o) , said side chain being of the formula -R 1 [-B-R*-] L-G, as defined above, wherein general structure I further includes at least one substitution selected from the group consisting of 15-halo, 16-halo, a 15,16 bridge atom (preferably carbon), a 14,15 bridge atom (preferably oxygen) , and a 16-pi-bonded lower alkyl. In certain embodiments, the antiandrogen utilized in the present invention may be represented by the general formula: wherein the dotted lines represent optional double bonds; wherein R lβ is hydrogen or lower alkyl, R 1J is absent, hydrogen or methyl in β position, iT is selected from the group consisting of hydrogen, hydroxyl, lower alkanoyloxy, lower alkyl, lover alkenyl, lover alkynyl, halo(lover)alkyl, halo(lower)alkenyl, halo(lower)alkynyl and fluoro- Cβ) substituted aromatic ring, and a moiety which, together vith R 1T forms R 17 (B ψ ) is selected from the group consisting of hydroxyl, (C j -C, 0 ) alkanoyloxy, (C,-C 7 )alkenoyloxy, (C,-C 7 )alkynoyloxy, aroyloxy, alkenoylo- xy, cycloalkenyloxy, 1-alkyloxy-alkyloxy, 1-alkyloxycycloalkyloxy, alkyl- silyloxy, carboxyl, alkanoyl and a moiety which together with R 1 , forms Antiandrogens useful in the combination therapy of the invention also include but are not limited to fluta ide (available from Schering-Plough Corp., Kenilworth, New Jersey, under trade name EULEΣIN) , Nilutamide (available from Roussel of Paris, France, under trade name ANANDRON) , cyproterone acetate (available from Schering AG, Berlin under trade name ANDROCUR) , Casodex available from ICI Pharmaceuticals, Macdesfield, England. Preferably, the antiandrogen has, as part of its molecular structure, a substituted or unsubstituted androgenic nucleus, and as another part of its molecular structure, the side-chain -R* C-B-R*-] L-G as defined above. Numerous syntheses of the preferred compounds set forth in the U.S. patent application of Labrie and Merand entitled "Androgen Derivatives for use in the inhibition of sex steroid activity" which is being executed on even date herewith, the entire disclosure of which is hereby incorporated by reference as though fully set forth herein. A preferred antiandrogen is EH 101 (x - 10) which may be synthesized as set forth below. Example 1 Synthesis of N-butyl, N-methyl-ll-(17 τ β-hydxuxy- "-androsten-3'-on-7'α- yl) undecanamide (EM 101) (5, x-10) (Scheme 1) πβ-acetαxy-yα-dl'-hydrocry tmdecaπyl)-4-androsten-3-one (2) Under argon atmosphere, in a flame dried apparatus with magnetic stirrer, a solution of 11-bromo undecanol tetrahydropyranyl ether (25 g, 74 mmol) in anhydrous THF (150 ml) was added dropwise to iodine-activated magnesium (1.9 g) .The mixture vas kept at room temperature overnight and then was cooled to -30'C and anhydrous cuprous chloride (0.3 g) was added quickly. After 45 min of strirring at this temperature, commercial 4,6- androstadien-17β-ol-3-one acetate (1) (10 g, 30.5 mmol) in anhydrous THF (100 ml) was added dropwise during 4 h. After 35 min, acetic acid (6 ml) and water (100 ml) was added. The mixture was allowed to reach room temperature and was stirred overnight. Afterwards, the organic com¬ pound vas extracted with ether (3X) . The organic layers were washed with water, dried on magnesium sulfate and evaporated. The residue was dissol¬ ved in acetic acid (35 ml) and water (100 ml) and kept 48 h at room tem¬ perature. And then, the organic compounds were extracted with ether (3X) . The organic layers were washed vith saturated sodium bicarbonate solution and water, dried on magnesium sulfate and evaporated. The product was purified by Silica gel dry column chromatography (Kieselgel, 60F254, Merk, 0.063- 0.200 mm, 150 g) . Elution with a mixture of methylene chlo¬ ride and ethyl acetate (20:1 v/v) gave 17β-acetoxy-7α-(ll , -hydroxy-unde- canyl)-4-androsten-3-one (2a, 1.46 g, 2.8 mmol, 9.22) as a colorless oil;- IR υ „ neat 3450, 1740, 1685, 1620 and 1245 cm- 1 ; NMR 0.84 (s, 3H, max 18'-CH,), 1.21 (s, 3H, tt'-CH,), 2.05 (s,3H, OCOCH,), 3.61 (t, 2H, J=6.59 Hz, H-C.l'). 4.61 (t, IH, J-7.69 Hz, H-C.17) and 5.73 (s, IH, H-C.4) and 17β-acetoxy-7fi-(11'-hydroxy undecanyl)-4-androsten-3-one (2b, 0.9 g, 1.7 mmol, 5.6%) as a colorless oil. ll-(17 , β-acetuxy * ^4*-a_ndrosteπ-3*-onτ-7 , α-yl) undecanoic acid (3) To 17β-acetoxy-7o-(11'-hydroxy undecanyl)-4-androsten-3-one (2a, 800 mg, 1.6 mmol) 'dissolved in acetone (50 ml) and cooled to 0*C was added under stirring during 5 min, a solution of Jones' reagent (8N chromic acid solution) (0.283 ml). After 15 min, isopropanol (0.5 ml) was added followed by water and the mixture was extracted with ethyl acetate (3X) . The organic layers were washed with brine, dried on magnesium sulfate and evaporated to dryness under reduced pressure. The crude ll-(17 , β-aceto^r-4'-androsten-3 , -on-7 , α-yl) undecanoic acid (3) (740 mg) vas used in the next step without purification. H-butyl, N-«t-hyl-ll-(17'β-acβtc_xy*-4'-ι__αιd^ undecana- To a solution of the above undecanoic acid derivative 3 (390 mg, 0.78 mmol) in anhydrous methylene chloride (8 ml) cooled at -10*C was added, under stirring, triisobutylamina (240 μl) and isobutylchlorofor¬ nate (140 μl). After 30 min, N-methylbutylamine (1.8 ml) was added and the mixture was stirred at room temperature for 1 h. Methylene chloride was added. The organic solution was washed with IN hydrochloric acid, water, saturated sodium bicarbonate solution and finally with water, dried on magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (Kieselgel, 60F254, Merck, 0.063-0.200 mm, 20 g) . Elution with a mixture of diethyl ether and methylene chloride (1:20, v/v) gave N-butyl, N-methyl-ll-(17 , β-acetoxy-4 , -androsten-3*-on- 7'α-yl) undecanamide 4 (230 mg, 0.39 mmol, 46% for the alcohol ( 2a )) as a colorless oil; IR υ neat 1740, 1680, 1640 and 1240 max cm- - : NMR 0.84 (s, 3H, 18'-CH,) f 0.95 (t, 3H, J-6.93 Hz, N-(CH,),CH,) , 1.21 (s, 3H, 19 » -CH,), 2.04 (s, 3H, OCOCH,) , 2.91 and 2.97 (2s, 3H, N-CH,). 3.26 and 3.36 (2t, 2H, J-7.86 Hz, N-CH,C,H T ), 4.61 (t, IH, J-8.42 Hz, H-C.17') and 5.72 (s, IH, H-C.4'). N-butyl, N ; -π-et-hyl-ll-(17 , β-hyd-κa-y-4 , -androsten-3 , -on-7 , o-yl) undec- anan de (5) (EH 101) The above acetoxy amide 4 (170 mg, 0.29 mmol) was dissolved in methanol (20 ml) and 65 potassitim carbonate (2 ml) and heated at 65*C for 200 min. After cooling, acetic acid (1 ml) and water (150 ml) were added and the mixture was extracted with ethyl acetate (3X) . The organic layers were washed with water, dried on magnesium sulfate and evaporated to dryness. The residue was purified by*Silica gel dry column chromatography (Kieselgel, 60F254, Merk, 0.063-0.200 mm, 20 g). Elution with a mixture of diethyl ether and methylene chloride (1:9, v/v) gave N-butyl-N-methyl- ll-(17^-hydroxy-4*-androsten-3'-on-7O-yl) undecanamide (EM 101, 94 mg, 0.17 mmol, 582) as a colorless oil; IR υ (neat) 3400, 1670 and 1640 max αn- i ; NMR 0.80 (s, 3H, 18'-CH 3 ), 0.95 (t,3H, J-6.75 Hz, - H,),^) , 1.21 (s, 3H, 19'-CH 3 ), 2.91 and 2.97 (2s, 3H, N-CH 3 ), 3.25 and 3.35 (2t, 2H, J-7.3HZ, N-CH,C 3 H 7 ), 3.67 (t, IH, J-8.18, H-C.17') and 5.72 (s, IH, H-C.4'). SCHEME I α 7B-H b 7α-H EM 101 (x - 10) Sex steroid formation inhibitors useful in the combination therapy of the invention include but are not limited to inhibitors of 5α-reducta- se activity, inhibitors of 17β-hydroxysteroid dehydrogenase activity, inhibitors of 3β-hydroxysteroid dehydrogenase activity and inhibitors of aromatase activity. A typically suitable 5α-reductase inhibitor is MK-906, a product of Herck, Sharp & Dohme (Mc Connell et al., J. Urol. 141: 239A, 1989). Another inhibitor of 5o-reductase is 17β-N,N-diethylcarbamoyl-4-methyl-4- aza-5α-androstan-3-one (4-MA) (Brooks et al., Endocrinology 109: 830, 1981; Liang et al., Endocrinology 112: 1460, 1983). Other 4-azasteroids acting as 5α-reductase inhibitors can be formed in Liang et al., J. Biol. chem. 259: 734-739, 1984; and in Brooks et al.. Steroids 47: 1-19, 1986, 6-methylene-4-pregnene-3,20-dione has also been described as 5α-reductase inhibitor (Petrow et al., J. Endocrinol. 95: 311-313, 1982). Similar properties have been described for 4-methyl-3-oxo-4-aza-5α-pregnane-30(s) carboxylate (Kadohama et al., J. Natl. Cancer Inst. 74: 475-486, 1985). Trilostane and epostane have been described as inhibitors of 3β-hy- droxysteroid dehydrogenase activity (Ernshav et al., Clin. Endocrinol. 21, 13-21, 1984; Robinson et al., J. Steroid Biochem. 21, 601-605, 1984; Lambert et al., Ann. Clin. Biochem. 23, 225-229, 1986; Potts et al., Ste¬ roids 32, 257-267, 1978) and have been successfully used for the treat¬ ment of breast cancer in combination with corticosteroids (Beardwell et al.. Cancer Chemother. Pharmacol. 10: 158-160, 1983; Williams et al.. Cancer Treat. Rep. 71, 1197-1201, 1987). 4-MA, (17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one) has been found to inhibit 3β-hydroxysteroid dehydrogenase activity in granulosa cells (Chan et al., Biochem. Biophys. Res. Commun. 144, 166-171, 1987). Epostane has been shown to inhibit 3β-hydroxysteroid dehydrogenase activity in pregnant goats (Taylor, J. Endocrinol. 113, 489-493, 1987). Preferred inhibitors of 17β-hydroxysteroid dehydrogenase activity include but are not limited to: N-butyl, N-mel±yl-ll-(16 , o-chloro-3' ,17 , β-dilη drαay estra-1' ,3 * ,5 * (10')- trien-7'α-yl) unjtecananri.de ("EM 139") . N-n-butyl-N-nethyl-ll-(16'α-chloro-3 ' ,3* ,5 » (10')- trien-7'α-yl) undecanamide ("EM 170") l^-n butyl • -«-βeth l-ll-{16 , o-bro«»-3•,17 , o-d-L_Iyd^α y-es1-^a-l , ,3',5'(10')- trien-7'α-yl) undecanamide ("EM 171") Examples of certain synthesis schemes for EH 139, EH 170 and EH 171 are set forth below (see example 2 and schemes 2 and 3) . Those of skill in the art will recognize analogous schemes for synthesizing analogous com ounds. XUEflQBD Q 2 SYNTHESIS OF PREFERRED SEX STEROID ACTIVITY TUHIH1TURS Synthesis of a starting componnri, N-n-butyl, N-αethyl-ll-(3'-benzoyloxy- 17 , -ox&-estra-l , ,3 , ,5 , (10 , )-triett- 7 -α-yl) ndecanamide (14a) (SCHEME 2) 19-nor-testosterone acetate 3-enolacetate (7) In an apparatus supplied with a drierite drying tube, a solution of 19-nor-testosterone (6) (100 g; 0.365 mole) in acetic anhydride (200 ml) , pyridine (32 ml) and acetylchloride (320 ml) was heated at reflux under magnetic stirring, for 3 h and then concentrated to dryness under vacuum. The dry residue was triturated in absolute ethanol, filtered and washed vith little portions of absolute ethanol. After drying, 19-nor- testosterone acetate 3-enolacetate vas obtained as a white powder (121.4 g, yield 93X) mp. 176-177'C. The structure was confirmed by spectroscopic means. 17β-acetoxy-estra-4,6-dien-3-one (8) To a cooled suspension of enolacetate (121 g; 0.337 mole) in a mixture of DMF (330 ml) and vater (7.2 ml) at 0"C vas added, under nitro¬ gen, over a period of 1 h, N-bromosuccinimide (63 g). The resulting solu¬ tion was stirred for an additional 0.5 h at 0*C. Then lithium carbonate (60.8 g) and lithium bromide (30.4 g) were added. The mixture vas heated at 95 # C for 3 h and then poured into 1.7 1 of ice-cold water containing 165 ml of glacial acetic acid. After stirring during 15 hours, the crude 17β-acetoxy-estra-4,6-dien-3-one (8) was filtered, washed with water. dried in a desiccating apparatus and recrystallized twice from isopropyl ether (72 g, yield 682, mp llO'C). The structure was confirmed by spec¬ troscopic means. 7o-(ll*-acetoxy-undecyl) 17β-acetoxy estra-4-en-3-one (9) A. Preparation of reagents and solvents 11-bromo undecanol tetrahydro pyranyl ether 11-bromo-undecanol (100 g, 398 mmol) was dissolved in dry ether (768 ml) and the solution was cooled to O'C using an ice/H,0 bath. To this solution was added HCl gas (2.13 g, 58.4 mmol, 26 ml of HCl/ether) . To this mixture, a solution of 3, -dihydro-2H-pyran (39.9 g, 43.3 ml) freshly distilled in dry ether (218 ml) was added over a period of 90 min. The solution was then stirred over a period of 16 hours at room temperature. Afterwards, sodium bicarbonate vas added to the mixture. The residue vas filtered and the solvent vas evaporated under vacuum. The product vas then filtered through basic alumina (250 g, Woelm, grade II) using petroleum ether (30-60) as solvent (112 g, 812). B. Grignard reagent In a dry three-neck flask (1000 ml) under dry argon, magnesium (12.0 g, 494 mmol) vas placed and activated vith iodine. Magnesium vas heated vith the flame to remove iodine and to dry the apparatus. The system was then cooled to -20*C, and a solution of 11-bromo-undecanol tetrahydro pyranyl ether (73;8 g, 211 mmol) in dry THF (420 ml) was added dropwise. The mixture was stirred under dry argon during one day at -20'C. The mixture was cooled to -35*C (±2*C) using a dry ice/CCL 4 /acetone bathv The anhydxous cuprous chloride (1.18 g, 12 mmol) was added and the mixture was stirred over a period of 0.5 h. C. Addition of Grignard reagent After 0.5 h, using the same apparatus mentioned above (Ar, -35 β C), a solution of 17 β-acetoxy estra-4,6-diene-3-one (8) (32.0 g, 102 mmol) in dry THF (300 ml) vas added dropwise over a period of 6 h to the Grignard reagent (red coloration appeared and disappeared) . The mixture was stirred for an additional 1 h and, after removal the cooling bath, acidified (about 0°C) with acetic acid (40 ml) , diluted with water and extracted with ether (3x) . The ether solution was washed with a saturated sodium bicarbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to dryness. The residue was dissolved in MeOH (660 ml) and 5N HCl (180 ml), refluxed for 1 h and 45 min, then concentrated under reduced pressure and cooled in an ice bath. The mixture vas then filtered to remove the white precipitate. After the solution had been diluted vith vater and extracted vith methylene chloride (3x) , the organic layer vas dried over anhydrous HgS0 4 and evaporated under reduced pressure to dryness. Finally, the pro¬ duct (55.9 g, brown oil) was chromatographed on silica gel (Kieselgel 60F254, Merck, 0.063-0.200 mm, 1500 g). Elution with mixtures of methyle¬ ne chloride and ethyl acetate (4:1 to 1:2 v/v) and then pure ethyl aceta¬ te gave crude 7α-(ll'-hydroxy-undecyl)-17β-hydroxy estra-4-en-3-one (34.8 g) which was dissolved in dry pyridine (200 ml) and dry acetic anhydride (200 ml) , stirred 17 h at room temperature and then poured in ice-water. The product was extracted with methylene chloride (3X) , washed with IN hydrochloric acid, water, saturated sodium bicarbonate and water (3X) , dried on anhydrous magnesium sulfate and filtered. After evaporation of solvent, the mixture (35 g) of 7 - and 7β-diacetoxyenones and degradation products of Grignard reagent were separated by flash chromatography on 1/00733 28 silica gel (Kieselgel 60, Merck, 230 mesh ASTM, 2.0 kg) developed with a mixture of hexane and diethyl ether (2:3 v/v) . The first product eluted was pure amorphous 7o-(ll'-acetoxy undecyl) 17β-acetoxy-estra-4-en-3--one, (9) (20.8 g, 39.4 mmol, yield from dienone was 39.02). Further elu¬ tion gave the 7 β-isomer (10) (5.4 g, 10.3 mmol, 102). All structures were determined by spectroscopic means. 7α-(ll'-hydroxy-undecyl) estra-l,3,5(10)-trien-3,17β-diol (11a) Under dry argon, a solution of 7α-(ll'-acetoxy undecyl) 17β-acetoxy- estra-4-en-3-one (9) (17.0 g, 32.4 mmol) in dry acetonitrile (150 ml) was added rapidly to a suspension of cupric bromide (14.8 g, 66.2 mmol) and mmol) and lithium bromide (2.89 g, 33.6 mmol) in warm acetonitrile (75 ml). The mixture was heated to reflux over a period of 30 min and stirred vigorously, and then cooled to room temperature. A saturated aqueous solution of sodium bicarbonate (50 ml) vas added, and then the organic compound vas extracted with ethyl acetate (3x 150 ml). The,orga¬ nic layers were washed with water, dried over anhydrous magnesium sulfa- te, filtered and evaporated under vacuum to dryness. The residue was chromatographed on silica gel (Kieselgel 60F254 Merck 0.063-0.200 mm; 1000 g). Elution with hexane-ethyl acetate (1:1 v/v) gave the 7α-(ll'- acetoxy-undecyl) estra-1' ,3' ,5' (10')-trien-3,17β-diol, 17β-acetate (lib) (8.51 g; 50.32) and the starting product (1.33 g; 152). The above diacetate phenol (8.51 g, 16.2 mmol) was dissolved in me¬ thanol (90 ml) and sodium hydroxyde 302 (w/v) (9 ml) . The mixture was refluxed for 90 min under dry nitrogen. The solution was then concentrat¬ ed under vacuum and diluted with hydrochloric acid (102 v/v) . The mixture was extracted using ethyl acetate (4 x 150 ml) and the ethyl ace¬ tate extract was washed with water, dried over anhydrous magnesium sulfa¬ te, filtered and evaporated under vacuum. The evaporation gave 7α-(ll'- hydroxy undecyl) estra-l,3,5(10)-trien-3,17β-diol (11a) (6.99 g, 982 brut) as a yellow foam, the structure of which was confirmed by spectros¬ copic means. 3-benzoyloxy 7α-(11'-hydroxy undecyl) estra-l,3,5(10)-trien-17β-ol (12) The above triol (6.99 g; 15.8 mmol) was dissolved in acetone (25 ml) and an aqueous solution of sodium hydroxyde (IN, 19.1 ml). The mixture was cooled to 0*C using an ice/water bath. Benzoyl chloride (2.22 ml, 19.1 mmol) was then added dropwise. The mixture was stirred for 40 min at 0*C and then diluted with water. The solution vas extracted using ethyl acetate (3X) and the organic layers vere vashed vith a saturated aqueous solution of sodium bicarbonate and finally vith vater. The ethyl acetate solution vas dried over anhydrous magnesium sulfate, filtered and evapo¬ rated under vacuum to dryness. Then, the residue vas immediately chroma¬ tographed on silica gel (Kieselgel, 60F254, 0.063-0.200 mm; 500 g) . The chromatography was carried out, first, using methylene chloride as sol¬ vent (about 1 liter) and secondly the pure 3-benzoyloxy 7α-(11*-hydroxy undecyl) estra-l,3,5(10)-trien-17β-ol (12), colorless oil (6.50 g, 752) was eluted with methylene chloride-ethyl acetate (5:1 about 1 liter and 4:1; v/v). The structure was confirmed by spectroscopic means. ll-(3'-benzoyloxy-17 , -oxo-estra-l' ,3* ,5' (10')-trien-7'α-yl) undecanoic acid (13) To a cooled solution of 3-benzoyloxy-7α-(11'-hydroxy undecyl)estra- l,3,5(10)-trien-17β-ol (12) (4.3 g) in acetone (100 ml) was added dropwise Jone's reagent (8N-chromic acid solution, 6.7 ml). After 30 min, isopropanol (40 ml) was added and the mixture was concentrated under vacuo. Water was added and the mixture was extracted four times with ethyl acetate. The organic layers were washed twice with brine, dried over magnesium sulfate and evaporated to dryness. The crude ll-(3'-ben- zoyloxy-17'-oxo-estra-l' ,3' ,5'(10')-trien-7'o-yl) undecanoic acid (13) (3.94 g) was used in the next step without purification. 37 11a R s H 12 -ifbutyl, -methyl-11- 3 , -h drαx -17 , -oxo-estr -^ , ,3',5 » (lO')-trien- 7'α-yl) undecanamide (14b) To ll-(3'-benzoyloxy-17'-oxo-estra-l*,3 , ,5'(10 , )-trien-7 , α-yl) unde¬ canoic acid (13) (3.94 g, 7.22 mmol), dissolved in anhydrous CH,C1, (100 ml) and cooled at -10*C vas added tributylamine (2.18 ml, 9.15 mmol) and isobutylchloroformate (1.30 ml, 10.0 mmol). The solution was stirred during 35 min. and N-methylbutylamine (13 ml, 109.7 mmol) was added. The mixture was warmed to room temperature and stirred during 1 h. Afterward, CH,Cl j was added and the organic phase was washed with IN HCl, water, saturated sodium bicarbonate solution and finally with water, dried with anhydrous MgS0 4 and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel. Elution with mixtu¬ re of EtOAc/hexane (1.5:8.5 v/v) yielded N-butyl, H-methyl-ll-α'- ben¬ zoyloxy-17'-oxo-estra-1* .S'.S'dO'j-trien^'o-yl) undecanamide (14a) (4.25 g, 962) as colorless oil; IR v (neat) 1750, 1725 and 1640 cm- 1 . The above described benzoyloxy amide (341 mg, 0.54 m ol) was dissolved in methanol (10 ml) and cooled at 0*C. Following this 2N NaOH (5 ml) was added and the mixture vas stirred during 60 min. at 0*C. The solution vas neutralized vith IN HCl and extracted vith CH 3 C1 3 . The organic phase vas dried vith anhydrous MgS0 4 and the solvent vas removed under reduced pressure. The residue vas purified by chromatography on silica gel. Elution vith mixture of EtOAc/hexane (3:7 v/v) yielded N-butyl, N-methyl- ll-(3'- hydroχy-17 , *****oxo-estra-r,3' ,4'(10)-trien-7'a-yl) undecanamide (14b) (284 mg, 972) as colorless oil; *H-NHR δ (CDC1 3 ) 0.91 (s.SH.lδ'-CH j ), 2.76 app(d,lHJ-16,3Hz, part of ABX system, 6'-H) 2.96 and 2.98 (2s,3H N-CH 3 ■»), 3.27 and 3.38 , 6.63 (broad s,lH,4'-H), 6.70 (broad d.lH.J- 8.5 Hz,2'-H), 7.12 (d,lH,J=8.4 Hz.l'-H); IR v (neat) 3270, 1730, 1615 cm- 1 ; MS m/e 523 (M*,1002), 508 max (M*-CH 3 ,322) , 142 (C 3 H 4 C0N(CH 3 )C,H, ♦ , 472). 16-ffAT.O-ESTRADIOL UNDECANAMIDE (SCHEME 3) N-n-butyl, N-n_ethyl-ll-(3\17 , -d_ cetαxy-estra-l»,3',5'(10*) ,16*-tetraen- 7'α-yl) iTnfjprnnmia.de (15) The ketone amide 14b (163 mg, 0.50 mmol) was dissolved in isoprenyl acetate (10 ml), p-toluenesulfonic acid (44 mg) was then added and the solution was distilled to about two-thirds of the original volume in 7 h and was then stirred at reflux for 12 h. Afterwards, the solution vas cooled with an ice-water bath and extracted with 50 ml of cooled ether. The ether was washed with a cooled satured sodium bicarbonate and water. The organic phase was dried with anhydrous HgSO t and the solvent was removed under reduced pressure. The residue vas filtered through alu¬ mina (15mm x 50 mm alumina Woehl neutral, activity II) using a mixture of benzene-diethyl ether (3:7 v/v) as eluant. The solvent vas removed under reduced pressure and, the residue vas purified by flash chromato¬ graphy on silica gel. Elution vith mixture of EtOAc/hexane (1:4 v/v) yielded the N-butyl, H-methyl-ll-α* .π'-diacetoxy-estra-l' ,3 » ,5' (10') , 16'-tetraen-7*α-yl) undecanamide (15) (244 mg, 802) as colorless oil; i H-NMR δ m (CDCl 3 ) 0.92 (s .SH.lβ'-CH,) , 0.92 and 0.95 (2t,3H,J » 7.0 Hz. tCH^ j CH j ), 2.18 (s,3H,17'-OCOCH 3 ) , 2.28(s,3H,3'-OC0CH 3 ) , 2.76 app (d,lH,J-16.1 Hz, part of ABX system,6'-H) , 2.90 and 2.96 (2s,3H,N-CH 3 ) , 3.26 and 3.35 (2t ,2H,J-7.6 Hz,N-CH,-), 5.52 (m,lH,16'-H) , 6.80 (broad app * s,lH,4'-H), 6.85 (dd.lH,J x -9.1 Hz and J 3 « 3.0 Hz,2'-H), 7.27 (d,lH,J » 9.1 Hz.l'-H); IR \> (neat) 1750, 1635, 1200 cm- 1 ; MS m/e 607 (M*,22), max 5(H » -COCH,,1002), SUBSTITUTE SHEET 550 (H*-C0CH 3 -CH 3 ,132), 523 (H'-2C0CH 3 ,452) , 142 (C 3 H 4 CON(CH 3 )C 4 H t *,552) , 129 (C 4 H,(CH 3 )NCOCH 3 \382), 114 (C,H, (CH 3 )NC0*, 602), 86 (C 4 H,(CH 3 )N*. 252): EXACT MASS calcd for C 3 ,H S7 0 s N 607.4239, found 607.4234. N-butyl, »-βetiyl-ll-(16 , α-chlo^o-3 , ae_etoαc_y-17 , -oxD-estra-l , ,3',4' (10')-trien»-7'α-yl) ττnriwpwnιmide (16, X - Cl) To diacetate amide 15, dissolved in 5 ml of acetone, was added a solution of sodium acetate (2.6 equivalents) in acetic acid and vater (1:11.3 v/v) and then, vas treated vith tertbutyl hypochlorite (1 eq.) prepared from t-butanol (4 ml) and Javel vater (Javex 6.12, 50 ml). The clear solution vas vanned to 55*C and stirred for 1 h. Afterwards, the solvent was evaporated to dryness. The residue was dissolved in ether (100 ml) and water was added (20 ml). The organic phase was washed vith vater, dried vith anhydrous MgS0 4 and evaporated to dryness. The residue vas purified-by chromatography on silica gel carried out vith mixture of EtOAc/hexane (3:7 v/v) to give the N-butyl, N-ββthyl-ll-de'α-chloro- S'-acβtoxy-^'-oxo-estra-l'.S'^'dO -trien^'α-yl) undecanamide 16, X-Cl) (115 m , 892) as colorless oil; l H-NMR \> (CDC1 3 ) 0.92 and 0.95 (2t,3H,J-7.0 Hz H(CH 3 ),CH J ), 0.96 (s.SH.lβ'-CH j ) , 2.28 (s,3H,3'-OCOCH s ) , 2.80 app (d,lH,J-16,6 Hz, part of ABX system, 6*-H) 2.90 and 2.96 (2s,3H,N-CH,), 3.24 and 3.35 (2t ,2H,J-7.4 Hz,-N-CH 3 -), 4.46 app (d,lH,J-6.6 Hz.lδ'β-H), 6.82 (broad s,lH,4'-H). 6.86 (dd,lH,J-9.1Hz and J.-.2.6Hz,2'-H), 7.29 (d,lH,J-9.1 Hz,l'-H) j IR \> (neat) 1750, 1640, * max 1205 cm- 1 ; MS m/e 601, 599 (H*,242, 682), 142 (C,H 4 C0N(CH 3 )C 4 H,*, 1002), 114 (C 4 H,(CH 3 )NC0*,932). SUBSTITUTE SHEET N-butyl, N-methyl-11-(16β-chloro-3 » ,17•-di ydxαxy-eatra-1' ,3• ,5 • (10•)- trien-7'α-yl) undecanamide ("EM 139") and ("EM 170") A stirred solution of haloketone amide (16, X**"C1) in anhydrous tetrahydrofuran (THF) (10 ml) under argon vas chilled to -70*C with 2-propanol/dry ice bath. A solution of 1.0 M of lithium aluminium hybride (2 eq.) vas then added dropwise. After 30 min, the reaction was allowed to return slovly at 0*C for 5 min, then vas quenched by the dropvise addition of a mixture of THF-EtOAc (5 ml) (1:1 v/v) and acidified at pH ^ 4 with (102) HCl. The mixture was stirring for 5 min at room temperature and then extracted with EtOAc. The organic phase was washed with water, dried on anhydrous Na 3 S0 4 and evaporated under reduced pressure. The residue was chromatographed on silica gel with a mixture of EtoOAc/hexane (4:6 v/v) as eluant: N-butyl, N-π_ethyl-ll-(16 , u-chlo^o-3 , 17 , α-dih droxy-estra-l , ,3' ,5' (10')- trien-7'α-yl) undecanamide ("EM 170") (15 mg, 292) as colorless oil; analytical sample was obtained by HPLC purification; i H- MR δ (CDC1,, 400 MHz) 0.79 (s.SH.lδ'-CH,) , 0.93 and 0.96 (2t, 3H,J=7.3 Hz,N(CH 3 ) 3 CH,) . 2.80 (2H,J,.,=17.1 Hz and J, f7 - 4.5 Hz, Δδ-24.34 (Hz, system ABX, 6'-H), 2.94 and 2.99 (2s, 3H.N-CH,), 3.26 (dd,J 3 - 7.6 Hz and J, - 7.4 Hz) and 3.32-3.43 (m)-[2H,-N-CH 3 -] , 3.71 (d,lH,J-4.5 Hz,17'β-H), 4.63 (ddd, IH, J χ ,, XI " 10.2 Hz, J χ ,, xτ - -4.5 Hz and J XifX , 3.9 Hz, 15'β-H), 6.50 (d, IH, J-24 Hz, 3'-OH), 6.60 (d, 1H.J-2.5 Hz, 4'-H), 6.66 (dd,lH,J x -8.4 Hz and J 3 -2.5 Hz, 2'-H), 7.14 (d,lH,J-8.5 Hz, l'-H); IR \ι (neat) 3300, 1615, 1495 cm" 1 ; MS m/e max 561,559 (M-, 402, 1002), 523 (M * -HC1, 202), 142 (C 3 H 4 C0N(CH 3 )C 4 H,*. 442), 114 (C 4 H,(CH 3 )CN0*. 372); Exact mass calculated for C 34 H S4 0 3 N'»C1 559.3785, found 559.3821: - and - -N-butyl, N-methyl-11-(16'α-chloro-3' ,17 ■ β-dihydroxy-estra-1'3' ,5* (10')- trien-7' -yl) undecanamide ("EM 139") (25 mg, 552) as a colorless oil; analytical sample was obtained by HPLC purification; IH-NMR δ (CDC1 3 , 400 MHz), 0.81 (s,3H, 18'-CH 3 ), 0.93 and 0.96 (2t, 3H,J=7.3 Hz, (CH 3 ) 3 CH 3 ), 2.78 (2H, J.,,-16.2 Hz and J g , 7 = 4.5 Hz, Δ»-24.34 Hz, system ABX, 6'-H), 2.94 and 2.99 (2s, 3H,N-CH 3 ) , 3.27 (dd, J x -7.6 Hz and J 3 -7.5 Hz) and 3.31-3.45 (M)[2H, -N-CH 3 -3 , 3.86 (dd, IH, J x ,, XT - 0H -3.4 Hz and J X7 , X , -5.9 Hz, 17'α-H), 4.11 (ddd, IH, J xi»ιs " 10«8 H*» J n»ιτ" 5 - 9 Hz ∞d 4«n < ddd » 1H » J ι»»ιs " 10 ' 8 Hz » J χ ,, xτ - 5.9 Hz and J x ,, XΪ -2.5 Hz, 16»β-H), 6.5$ (d, IH, J-19.7 Hz, 3'- OH), 6.61 (d, IH, J-2.5 Hz, 4»-H), 6.66 (dd, IH, J x -8.4 Hz and J 3 -2.6 Hz, 2»-H), 7.13 (d, IH, J-8.4 Hz, 1*-H); IR v (neat) 3320, 1615, 1490 max cm" 1 ; HS m/e 561,559 (M , 382, 1002), 523 (H*-HC1, 162). 142 (C 3 H 4 C0N(CH 3 )C 4 H,\ 802), 114 (C 4 H,(CH 3 )NCO ,762) ; exact mass calculated for C 34 H 14 0 3 N»»C1559.3785, found 559.3825. 37 Schema 3 14b: R«<CH j / 10 CON<CH 3 )C 4 H, 16 X»C1 ,8r EM 105 X«Br, R b «0H, R e »H DI 170 X«θr, R b -H, R e «0H Eϊl 139 χ«Cl f R b -0H, R c -H EB 171 X«Cl t R b -H, R C -OH Eϊl 156 X»I, R b -0H, R C -H N-a-butyl, N-J-_e1^1-ll-(16 , α-b^osιo-3 , -acetxιx-17 , -c«o-es r-l , ,3 » ,5'- (10'),trien-7*o-yl) undecanamide (16, X»Br) To the above diacetate 15 (244 mg, 0.40 mmol) dissolved in 10 ml of acetic acid was added dropwise with stirring within 10 minutes and at room temperature, a brominating solution composed of 50 mg (0.6 mmol) of sodium acetate, 1.6 ml of acetic acid, 0.04 ml of water and 63.9 mg (0.02 ml, 0.40 mmol) of bromine. During the course of this reaction, a red coloration appeared and disappeared. To the solution, 50 ml of ether was added and the organic phase was washed with water (4 x 50 ml) followed by a saturated sodium bicarbonate solution (2 x 50 ml) and finally with water (3 x 50 ml). The combined phase was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The residue was chromato¬ graphed on silica gel (Kieselgel, 60F254, Merck, 0.063-0.200 mm). Elu¬ tion vith a mixture of hexane-ethyl acetate (4:1 v/v) yielded N-butyl, N-mβthyl-ll-deα-bromo-S'-acetoxy-π'-oxo-estra-l',3',5'(10*),trien-7'-α- yl) undecanamide (16, X-Br) (201 mg, 782) as colorless oil (201 mg, 782), as colorless oil; -iH-NMR o (CDC1 3 ), 0.94 (s, SH.lδ'-CH,), 2.28 (s, 3H, 3'-0C0CH 3 ), 2.82 app (d,lH,J-16.4 Hz, part of ABX system, 6'-H), 2.90 and 2.96 (2s, 3H,fl*-CH, -), 3.24 and 3.35 (2tapp.2H, J-7.7 Hz, -N-CH 3 -), 4.58 (t,lH,J-3.6 Hz, 16β-H), 6.82 (broad s,lH,4'-H), 6.88 (dd,lH, J-8.0 Hz and J 3 « 4.0 Hz,2 f -H), 7.29 (d.lH,J-8.0 Hz, l'-H); MS m/e 644 (M*,72), 565 CM* - Br, 772), 522 (M*-Br-C0CH 3 , 552), 142 (C 3 H 4 C0N(CH j )C 4 H,\ 672), 114 (C 4 H,(CH 3 )NCO*, 662), 88 (1002). N-bu l, N-methyl-11-(16 ■ α-bromo-3',17'-diiydmiy-eatra-l',3,4'(10')- trien-7'α-yl) undecanamide ("EM 105") and ("EM 171") A solution of bromoketone amide 16 (X-Br) (295 mg, 0.46 mmol) in anhydrous tetrahydrofuran (10 ml) under argon vas chilled to -70*C and a solution of 1.0 M of lithium aluminium hybride in ether (0.92 ml, 0.92 mmol) vas added dropvise vith rapid magnetic stirring. After 30 min, the reaction vas quenched by the dropvise addition of a mixture of THF- ethyl acetate (1:1 v/v) and acidified by 102 hydrochloric acid. The mix¬ ture vas stirring for 5 min at room temperature and then extracted with ethyl acetate. The organic phase was washed with water, dried on anhy¬ drous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel. Elution vith a mixture of hexane-ethyl acetate (7:3 v/v) gave: N-n-butyl, N-methyl-11-(16*o-bromo-3 • ,17'α-dihydroxy-estra- 1' ,3' ,5•(10')-trien-7 • α-yl) undecanamide ("EM 171") (63 mg, 212) as colorless oil; -H-ΪB5R δ (CDC1 3 , 400 MHz) 0.81 (s, 3H, lβ'-CH,), 0.93 and 0.96 (2t, 3H.J-7.3 Hz.N(CH 3 ),CH 3 ) , 2.79 (2H,Jg g-16.6 Hz, Jg 7 -4.7 Hz, - Δδ-24.34 Hz, system ABX,6'-H), 2.94 and 2.99 (2s,3H,N- CH j ), 3.27 (dd,2H,J x -7.7 Hz and J 3 -7.5 Hz, -N-CH,-) , 3.31-3.44 (m,2H,-N- CH 3 -), 3.66 (dd,lH,J 17 17 -l-4 Hz, J χ7 16 « 4,3 Hz, 17'β-H), 4.68 (dt,lH,J 16 17 -4,3 Hz, , J χ6 15 » 9.7Hz,16'β-H) , 6.60 (d,lH,J-2.4 Hz, 4'-H), 6.65 (dd, 1H.J-8.5 Hz and J 3 -2.5 Hz, 2 f -H), 7.14 (d,lH,J-8.5 Hz, l'-H); IR v (neat) 3300, 1615, 1495 cm" 1 ; MS m/e 605,603 (M*. 172), max 523 (M*-HBr, 812), 142 (C 3 H 4 CON(CH 3 )C 4 H,*,1002) , 114 (C 4 H,(CH 3 )NC0\ 972)-; Exact mass calculated for C 34 H, 4 0 3 N'»Br 603.8289, found 603.3304. 4C and N-n-butyl, N-βe hyl-ll-(16 , α-brta-_o-3 17 l β- i-b _ro y-est^ -l , ,3',- 5'(10 , )-trien-7o-yl) nnrieα-manride ("EM 105") (170 mg, 502) as a colorless oil; analytical sample vas obtained by HPLC purification; - t H-NMR δ (CDC1 3 , 400 MHz), 0.80 (s,3H,18,-CH 3 ) , 0.93 and 0.96 (2t,3H,J-7.3 Hz,N(CH 3 ) 3 CH 3 ) , 2.80 (2H,J g 6 « 16.4,Jg ? -4.6 Hz, Δδ-24.34 Hz, system ABX, 6*-H), 2.94 and 2.99 (2s,3H,N-CH 3 ) , 3.27 (dd, 2H,J x -7.7 Hz and J 3 -7.5 Hz, -N-CH,-) , 3.31-3.45 (m,2H,-N-CH 3 -) , 4.02 (dd,lH,J 1? 17 - 3.7 Hz, and J χ? 16 -6.1 Hz, 17*e-H), 4.15 (ddd,lH,J 16 15 » 10.2 Hz, J χ6 17 - 6.1 Hz and J lfi χ5 -2.9 Hz, 16'β-H), 6.61 (d,lH,J-2.5 Hz, 4'-H), 6.66 (dd,lH,J-8.4 Hz and J 3 2.5 Hz, 2»-H) . 7.12 (d,lH,J-8.4 Hz, l'-H); IR υ (nut) 3320, 1610, 1490 cπr»; MS m/e 605, 603 (M*. max 292), 523 W-HBr, 1002), 142 (C 3 H 4 C0N(CH 3 )C % H,*. 702). 114 (C 4 H,(CH 3 )NC0-, 602); Exact mass calculated for C J4 H I4 0 3 N'«Br 603.3289, found 603.3289. Antiestrogens useful in the combination therapy of the invention include but are nor limited to Tamoxifen, commercially available from Imperial Chemical Industries, and EM 139, EM 170 and EM 171 whose synthe¬ sis are set forth above. Some steroidal antagonists also function as in¬ hibitors of sex steroid formation. The antiestrogens EH 139, EM 170 and EM 171, for example, exhibit the dual function of acting as sex steroid formation inhibitors. For this reason, a combination therapy requiring both an inhibitor of sex steroid formation and a steroidal antagonist may be produced by administering a single active compound (alone or together with diluent) capable of performing both functions. Another example of a dual function active ingredient is the antiandrogen EM 101 which has also shown an inhibitiory effect on sex steroid formation. The inhibitor of sex steroid biosynthesis is preferably capable of acting at least in peripheral tissues (extra-testicular and extra-adre¬ nal). In preferred embodiments, it is used in association vith an antian¬ drogen, and vith an LHRH agonist or LHHH antagonist. The use of an LHSH agonist is the more preferred method of chemical castration. Surgical castration may alternatively be used as a means of inhibiting testicular hormonal secretions, but chemical castration is preferred. By the term "LHSH agonist" is meant synthetic analogues of the natu¬ ral luteinizing hormone-releasing hormone (LHRH) , a decapeptide of the structure: L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl- gly- cyl-L-leucyl-arginyl-L-prolylglycyl-NH 3 . Typical suitable LHHH agonists include nonapeptides and decapeptides represented by the formula: L-pyroglutamyl-L-histidyl-L-tryptophyl-L- seryl-L-tyrosyl-X-Y-L-arginyl-L-prolyl-Z wherein X is D-tryptophyl, D- leucyl, D-alanyl, iminobenzyl-D-histidyl, 3-(2-naphthyl)-D-alanyl, 0-ter- butyl-D-seryl, D-tyrosyl, D-lysyl, D-phenylalanyi or N-methyl-D- alanyl and Y is L-leucyl, D-leucyl, N-^-raethyl-D-leucyl, N α -methyl-L- leucyl or D-alanyl and wherein Z is glycyl-NHR x or NHR X wherein R. is H, lower alkyl or lover haloalkyl. Lover alkyl includes, for example, methyl, Haloloweral yl includes, for example, -CF- 3 , -CH j CF, , -CF 3 CH 3 , and the like. Fluorine is a preferred halogen. Preferred nonapeptides wherein Y is L-leucyl and X is an optically active D-form of selected amino acids and Z is NHC 3 H, are [D-Trp* , des- Gly-NH, - ■ ]LHHH ethylamide (X-D-Trp«) ; [D-Ser-t-BuO)• , des-Gly-NH 3 - -]LHRH ethylamide [X-D-Ser(t-BuO«)] ; [D-Leu*, des-Gly-NH 3 - -]LHRH ethylamide (X » D-Leu*, [D-His(Bzl)*, des-Gly-NH 3 - -]LHRH ethylamide (X-iminobenzyl-D- His*) and [D-Ala«, des-Gly-NH 3 10 ]-LHRH ethylamide (X-D-Ala«). Preferred decapeptides include [D-Trp*]LHRH wherein X-D-Trp, Y-L- leucyl, Z-glycyl-NH 3 , [D-Phe*]-LHRH wherein X-D-phenylalanyl, Y=L-leucyl and Z-glycyl-HN 3 ) or [D-Nal(2)«LHRH which is [» J -3-(2-naphthyl)-D-Ala«]- LHRH wherein X-3(2-naphthyl)-D-alanyl, Y-L-leucyl and Z-glycyl-NH 3 . Other LHSH agonists useful within the scope of this invention are the α-aza analogues of the natural LHRH, especially, [D-Phe*, Azgly 1 ']- LHSH, [D-Tyr(-Me)*, Azgly lβ ]LHBH, and [D-Ser-(t-BuO)« , Azgly 1β ] HSH dis¬ closed by A.S. Dutta et al. in J. Med. Chem., 21, 1018 (1978) and U.S. Pat. No. 4,100,274 as veil as those disclosed in U.S. Fat. Nos. 4,024,248 and 4,118,483. Typical suitable LHSH antagonists include [N-Ac-D-p-Cl-Phe 1 ,***, D-Phe>, D-Arg*, D-Ala 1β ]-LHRH disclosed by J. Ercheggi et al., Biochem. Biophys. Res. Coππun. 100, 915-920 (1981); [N-Ac-D-p-Cl-Phe 1 ,* 1 , D-Trp - , D-Arg*. D-Ala 10 ]LHSH disclosed by D.H. Coy et al., Endocrinology, 110: 1445-1447 (1982); [N-Ac-D-(3-(2-naphthyl)-0Ala) - , D-p-Cl-Phe 1 , D-Trp 1 , D-hArg(Et ? )«, D-Ala i °]LHRH and [N-Ac-Pro -.- D-pF-Phe 1 , D-(3-(2-naphthyl)- Ala > ,*]-LHSH disclosed by J.J. Nestor et al. J. Steroid Biochem., 209no. 6B) , 1366 (1984); the nona- and decapeptide analogs of LHRH useful as LHRH antagonists disclosed in U.S. Pat. No. 4,481,190 (J.J. Nestor et al.)- analogs of the highly constrained cyclic antagonist, cycle [Δ 3 13- Pro 1 , D-p-Cl-Phe 1 , D-Trp J ,«, N-Me-Leu 7 , β-Ala l -]-LHRH disclosed by J. ivier, J. Steroid Biochem., 20 (no. 6B) , 1365 (1984); and [N-Ac-D-(3- (2-naphthpyD-Ala 1 , D-p-F-Phe 1 , D-Tr - , D-Arg*]LHRH disclosed by A. Corbin et al., J. Steroid Biochem. 20 (no. 6B) 1369 (1984). Preferred nonapeptides wherein Y is L-leucyl and X is an optically active D-form of selected amino acids and Z is NHC 3 H, are [D-Trp*, des- Gly-NH,* -]LHRH ethylamide (X-D-Trp«) ; [D-Ser-t-BuO) • , des-Gly-NH s - ■ ]LHRH ethylamide [X-D-Ser(t-BuO«)] ; [D-Leu* , des-Gly-NH 3 - ■ ]LHRH ethylamide (X-D-Leu«, [D-His(Bzl)*, des-Gly-NH, - -]LHRH ethylamide (X-iminobenzyl-D- His«) and [D-Ala*, des-Gly-NH, 10 ]-LHRH ethylamide (X « D-Ala«). Preferred decapeptides include [D-Trp*]LHRH wherein X-D-Trp, Y-L- leucyl, Z » glycyl-NH 3 , [D-Phe«]-LHRH wherein X-D-phenylalanyl, Y-L-leucyl and Z=glycyl-HN 3 ) or [D-Nal(2)*LHRH which is [•»-3-(2-naphthyl)-D-Ala«]- LHRH wherein X-3(2-naphthyl)-D-alanyl, Y-L-leucyl and Z-glycyl-NH 3 . Other LHRH agonists useful within the scope of this invention are the o-aza analogues of the natural LHRH, especially, [D-Phe*, Azgly 10 ]- LHRH, [D-Tyr(-Me)*, Azgly 0 ]LHRH, and [D-Ser-(t-BuO)*, Azgly 10 ]LHRH dis¬ closed by A.S. Dutta et al. in J. Med. Chem., 21, 1018 (1978) and U.S.¬ Pat. No. 4,100,274 as well as those disclosed in U.S. Pat. Nos. 4,024,248 and 4,118,483. Typical suitable LHRH antagonists include [N-Ac-D-p-Cl-Phe 1 , - , D-Phe 1 , D-Arg*. D-Ala 10 ]-LHRH disclosed by J. Ercheggi et al., Biochem. Biophys. Res. Commun. 100, 915-920 (1981); [N-Ac-D-p-Cl-Phe 1 , 1 , D-Trp 1 , D-Arg«, D-Ala 10 ]LHRH disclosed by D.H. Coy et al.. Endocrinology, 110: 1445-1447 (1982); [N-Ac-D-(3-(2-naphthyl)-0Ala) - , D-p-Cl-Phe 1 , D-Trp 1 , D-hAτg(Et,)«, D-Ala 10 ]LHRH and [N-Ac-Pro 1 , D-pF-Phe 1 , D-(3-(2-naphthyD- Ala*»,«]-LHRH disclosed by J.J. Nestor et al. J. Steroid Biochem., 20 9no. 6B),-1366 (1984); the none- and decapeptide analogs of LHRH useful as T LHRH antagonists disclosed in U.S. Pat. No. 4,481,190 (J.J. Nestor et al.); analogs of the highly constrained cyclic antagonist, cycle [Δ 1 Pro 1 , D-p-Cl-Phe 1 , D-Trp 1 ,*, N-Me-Leu', β-Ala - -]-LHRH disclosed by J. Rivier, J. STeroid Biochem., 20 (no. 6B) , 1365 (1984); and [N-Ac-D-(3-(2- naphthpyD-Al 1 , D-p-F-Phe 1 , D-Trp - , D-Arg«]LHRH disclosed by A. Corbin et al., J. Steroid Biochem. 20 (no. 6B) 1369 (1984). Other LHRH agonist and antagonist analogs are disclosed in LHRH and its Analogs (B.H. Vickery et al. eds, at pages 3-10 (J.J. Nestor), 11-22 (J. Rivier et al.) and 22-33 (J.J. Nestor et al.) as veil as in The Case for LHRH agonists (Clinical Oncology, Furr and Denis, eds), Bailliere Tindall, vol. 2, no. 3, pp. 559-570, 1988). The LHRH agonists and antagonists useful in this invention may con¬ veniently be prepared by the method described by Stewart et al. in "Solid Phase Peptide Synthesis" (published in 1969 by Freeman & Co., San Francisco, page 1) but solution phase synthesis may also be used. The nona- and decapeptides used in this invention are conveniently assembled on a solid resin support, such as 12 cross-linked Pro-merri- field resin by use of an automatic peptide synthesizer. Typically, side? chain protecting groups, well known to those in the peptide arts, are used during the dicyclohexylcarbodiimidecatalyzed coupling of a tert-bu- tyloxycarbonylamino acid to the growing peptide attached to a benzhydryl- amide resin. The tert-butyloxycarbonyl protecting groups are removed at each stage with trifluoroacetic acid. The nona- or decapeptide is cleaved from the resin and deprotected by use of HF. The crude peptide is puri¬ fied by the usual techniques, e.g., gel filtration and partition chroma¬ tography and optionally lyophilization. See also D.H. Coy et al., J. Med. Chem. 19, pages 423-425 (1976). In this invention, the LHRH agonist or antagonist, the 5α-reductase inhibitor, the antiandrogen, the antiestrogen, and, where applicable, the inhibitor of 3β- and 17β-hydroxysteroid dehydrogenase activities are administered as pharmaceutical compositions via topical, parenteral or oral means. The LHRH agonist or antagonist is administered parenterally, i.e., intramuscularly, subcutaneously or intravenously by injection or infusion by nasal drops or by suppository. The LHRH agonist or antagonist may also be microencapsulated in or attached to a biocompatable, biode¬ gradable polymer, e.g., poly(d,l-lactide-co-glycolide) and subcutaneously or intramuscularly injected by a technique called subcutaneous or intra¬ muscular depot to provide continuous, slow release of the LHRH agonist or antagonist over a period of 30 days or longer. The most preferred route of administration of the LHRH agonist or antagonist is subcutaneous or intramuscular depot injection. Preferably the antiestrogen will be admi¬ nistered orally. Preferably, the 5α-reductase inhibitor, the antiandro¬ gen, the antiestrogen, the inhibitor of 3β-HSD and the inhibitor of 17β- HSD can also be administered orally. The antiestrogen, an inhibitor of 3β-HSD and inhibitor of 17β-HSD can also be administered in a slow release formulation, e.g. poly(d,l-lactide-cσglycolide) or as implants. The amount of each component administered is determined by the attending clinicians taking into consideration the etiology and severity of the disease, the patient's condition and age, the potency of each component and other factors. According to this invention, the following dosage ranges are suitable. The LHRH agonist or antagonist is generally administered at from about 10 to 5000 μg per day with contemplated dosage ranges of about 10 to 1500 μg per day and about 250 (preferably 50 μg to 500 μg per day) for the LHRH agonist and to about 100 to 2000 μg per day for the LHRH antago¬ nist being preferred. In the most preferred embodiment of this invention, the LHSH agonist or antagonist is administered subcutaneously in a daily dose of 500 μg for the first 30 days and thereafter subcutaneously in a daily dose of 250 μg regardless of the patients' body weight. When the LHRH agonist or antagonist is administered, once every 30-day period is used, with a dose of 750 to 15,000 μg per 30-day period being preferred. Similar daily delivery doses are used for longer-term controlled release formulations. The inhibitors of 3β-HSD and 17β-HSD are preferably administered in dosages ranging from about 0.1 to 25 mg/kg per day with 200 mg per day in two equally divided doses being preferred. The antiestrogen compositions are administered in a dosage range of about 0.05 to 25 mg/kg body weight per day, with 20 mg, especially 40 mg, in two equally divided doses being preferred. The 5 -reductase inhibitor compositions are administered in a dosage ranging from 0.1 to 25 mg kg per day vith 50 mg per day in two equivalent doses being preferred. The antiandrogen and aro atase inhibitor compositions are administe¬ red in a dosage range of 0.5 to 25 mg/kg body weight per day with 750 mg per day in three equally divided doses being preferred. The LHRH agonist or antagonist, antiestrogen, antiandrogen, an inhi¬ bitor of aromatase, 17β-HSD and 3β-HSD each may be administered separate¬ ly or when the modes of administration are the same, all or at least two of them may be administered in the same composition, but in any case the preferred ratio of LHSH agonist to antiestrogen, to antiandrogen to inhi¬ bitor of 17β-HSD and administered daily will be about 250 μg of LHRH ago¬ nist to about 750 mg of antiandrogen, about 40 mg of antiestrogen, to about 40 mg of inhibitor of 17β-HSD and about 40 mg of inhibitor of 3β-HSD. In the therapy of prostate cancer, combining the administration of an LHRH agonist or antagonist, an antiestrogen, an antiandrogen and an inhibitor of 17β'HSD, the dosages preferable are as follows: the LHRH agonist or antagonist is generally administered at from about 10 to 2000 μg per day, with contemplated dosage ranges of 10 to 500 μg per day, 50- 250 μg per day and 250 to 500 μg per day being preferred. In the most preferred embodiment of this aspect of this invention, the LHRH agonist or antagonist is administered subcutaneously in a daily dose of 500 μg for the first 30 days and thereafter subcutaneously in a daily dose of 250 μg regardless of the patients' body veight. When the LHRH agonist or antagonist is administered, once every 30-day period, by intramuscular or subcutaneous depot injection, a dose from about 300 to 60000 (occasional¬ ly 10000) μg per 30-day period is used, with a dose of 750 to 2000 μg per 30-day period being preferred. The antiandrogen composition is generally administered in a dosage range of about 0.5 to 25 mg/kg (body weight) per day with 400 especially 750 mg per day in three equally divided doses being preferred. The antiestrogen and inhibitor of 17β-HSD and 3β-HSD activities are administered in a dosage range of about 0.1 to 25 mg/kg body weight per day, with 100 mg in two, preferably vith 50 mg in two, equally divided doses being preferred. The LHRH agonist or antagonist, antiandrogen, antiestrogen, 5 -re- ductase inhibitor, inhibitor of 17β-HSD, inhibitor of 3β-HSD, inhibitor of aromatase, each may be administered separately or when the modes of administration are the same, all or two or three of them may be adminis¬ tered in the same composition, but in any case the preferred ratio of LHRH agonist to antiandrogen to antiestrogen administered daily will be about 750 μg of LHSH agonist to about 250 mg of antiandrogen to prefera- b 1y 40 mg of antiestrogen. In the therapy of prostate cancer, according to this invention, it is preferred that the LHRH agonist is [D-Trp*, des-Gly-NH, 10 ]LHRH ethyl¬ amide be administered subcutaneously in single daily dose of 500 μg for the first thirty (30) days of treatment and thereafter in a single daily dose ' of 250 μg. SUBSTITUTE SHEET In the combination therapy of prostate cancer according to this invention,., the administration of the antiandrogen, antiestrogen, inhibi¬ tor of 17β-HSD, inhibitor of 5α-reductase, inhibitor of aromatase, and inhibitor of 3β-HSD, LHRH agonist or LHSH antagonist can be started in any order of sequence. Preferably, the administration of the antiandrogen and 5α-reductase inhibitor, are started before (preferably two to four hours before) the administration of the LHSH agonist or LHSH antagonist is started. Orchiectomy can replace LHRH agonist or antagonist. Preferably, the administration of the inhibitor of 17β-HSD and inhibitor of 3β-HSD is started on the same day as the administration of the LHRH agonist or LHRH antagonist. However, the attending clinician may elect to start adminsitration of the LHRH agonist or antagonist simultaneously with the antiandrogen, antiestrogen inhibitor of 17β-HSD and inhibitor of 3β-HSD. When patients whose testes have already been surgically removed are treated according to this invention, the administration and dosage of the antiandrogen and the other components of the therapy (except the LHRH agonist or antagonist which is not used) are the same as indicated for the therapy in which the LHRH agonist or antagonist is used. The LHRH agonists or antagonists useful in the present invention are typically amorphous solids which are freely soluble in water or dilute acids, e.g., HCl,' H,S0 4 , citric, acetic, mandelic or fumaric. The LHRH agonist or antagonist for subcutaneous injection is supplied in vials containing 5 ml of sterile solution with the LHRH agonist or antagonist at a concentration of about 1.0 mg/ml. A typical pharmaceutical composition of the LHRH agonist or antago¬ nist includes the LHRH agonist or antagonist or a pharmaceutically acceptable acid salt thereof, benzyl alcohol, a phosphate buffer (pH 6.0-6.5) and sterile water. The LHRH agonist or antagonist for intramuscular or subcutaneous depot injection may be microencapsulated in a biocompatible, biodegrada¬ ble polymer, e.g., poly (d,l-lactide-co-glycolide) by a phase separation process or formed into a pellet. The microspheres may then be suspended in a carrier to provide an i jectable preparation or the depot may be injected in the form of a pellet. See also European patent application EPA No. 58,481 published Aug. 25, 1982 for solid compositions for subder- mal injection or implantation or liquid formulations for intramuscular or subcutaneous injections containing biocompatible, biodegradable polymers such as lactide-glycolide copoly er and an LHRH agonist, e.g. D-Ser-t- BuO*, Azgly lβ -LHRH. These formulations permit controlled release of the peptide. The inhibitors of 17β-HSD, 3β-HSD, aromatase and 5α-reductase are typically compounded in customary ways for oral administration, e.g., in tablets, capsules and the like. These compounds useful in the present invention are typically formulated with conventional pharmaceutical exci- pients, e.g., spray dried lactose and magnesium stearate into tablets or capsules for oral administration. The antiestrogens, when used with the invention, are typically compounded in customary ways for oral administr¬ ation, e.g., in capsules, tablets, as dragees or even in liquid form, e.g., suspensions or syrups. One or more of the active substances, with or without additional types of active agents, can be worked into tablets or dragee cores by being mixed vith solid, pulverulent carrier substan¬ ces, such as sodium citrate, calcium carbonate or dicalcium phosphate, and binders such as polyvinyl pyrrolidone, gelatin or cellulose derivati¬ ves, possibly by adding also lubricants such as magnesium stearate, sodium lauryl sulfate, "Carbovax" or polyethylene glycols. Of course, taste-improving substances can be added in the case of oral administra¬ tion forms. SUBSTITUTE SHEET The therapeutically active antiestrogen compound should be present in a concentration of about 0.5-902 by weight of the total mixture, i.e., in amounts that are sufficient for maintaining the above-mentioned dosage range. As further forms, one can use plug capsules, e.g., of hard gelatin, as well as closed soft-gelatin capsules comprising a softener or plasti- cizer, e.g. glycerine. The plug capsules contain the active substance preferably in the form of granulate, e.g., in mixture with fillers, such as lactose, saccharose, mannitol, starches, such as potato starch or amylopectin, cellulose derivatives or hightly-dispersed silicic acids. In soft-gelatin capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as vegetable oils or liquid polyethy¬ lene glycols. In place of oral admin stration, the active compounds may be admini¬ stered parenterally. In such case, one can use a solution of the active substance, e.g., in sesame oil or olive oil. One or more of the active substances (antiestrogen or inhibitor of 17β-HSD and 3β-HSD can be microencapsulated in or attached to a biocompatible, biodegradable polymer, e.g. poly(d,l-lactide-co-glycolide) and subcutaneously or intra¬ muscularly injected by a technique called subcutaneous or intramuscular depot to provide continuous slow release of the compound(s) for a period of 2 weeks or longer. EET In the most preferred aspect of this invention, the LHRH agonist is [D-Trp*,des-Gly-NH,* ■• >] LHRH ethylamide which is administered subcuta¬ neously in single daily dose of 500 μg for the first thirty (30) days of treatment and thereafter in a single daily dose of 250 μg: the antian¬ drogen is EM 101 which is administered orally in three equally divided daily doses of 250 mg; and the inhibitor of sex steroid biosynthesis is EM 139 and/or MK 906 administered orally in two equally divided doses of 50 mg every 12 hours. The inhibitor(s) of sex steroid biosynthesis and the antiandrogen are preferably administered to a male in need of the prostate cancer treatment of this invention two to four hours before the LHRH agonist or antagonist is administered, but the at tending clinician may elect to start administration of the LHSH agonist or antagonist, the antiandrogen and the inhibitor of steroid biosynthesis simultaneously. When the antiandrogen and sex steroid inhibitor are particularly effective, both chemical (LHRH agonist or antagonist) and surgical castration may be avoided. Especially, when patients whose testes have already been surgically removed are treated according to this invention, no LHRH agonist or antagonist need to be used but other dosages remain the same. The terms and descriptions used herein are preferred embodiments set forth by way of illustration only, and are not intended as limitations on the many variations which those of skill in the art will recognize to be possible in practicing the present invention as defined by the following claims. STITUTE SHEET

Claims: 1. A method for treating prostate cancer in humans or other warm-blooded animals in need of such treatment, said method comprising the steps of blocking androgen receptors by administering a therapeutically effective amount of an antiandrogen having, as part of its molecular structure, a substituted or unsubstituted androgenic nucleus of the formula: and having as another part of its molecular structure, at least one side chain represented by the formula: -R 1 [-B-R 1 -] L-G said chain being substituted onto said androgenic nucleus at a position selected from the group consisting of 6, 7, 14, 15, 16 and 17, wherein: x is an integer from 0 to 6, wherein at least one of L and 6 is a polar moiety distanced from said ring carbon by at least three interven¬ ing atoms, and wherein: R 1 and R 2 are independently either absent or selected from the group consisting of straight- or branched-chain alkylene, straight- or branched chain alkynylene, straight- or branched-chain alkenylene, phenylene and fluoro-substituted analogs of the foregoing; B is either absent or selected from the group consisting of -0-, -S-, -Sβ-, -SO-, -SO,-, -NR»-, -SiR**,-, -CR»0R»-, -NR'CO-, -NR>CS-, -C0NR 1 -, -CSNR 1 -, -C00-, -COS-, -SCO-, -CSS-, -SCS-, -OCO- and phenylene (R 1 being hydrogen or lower alkyl) ; L is either a moiety which together with G, forms a heterocyclic ring having at least one nitrogen atom or is selected from the group consisting of lover alkyl, -CONR*-, -CSNR*-. -NR"C0-, -NR«CS-, -NR'CONR*- NR« n -NR*C-NR*- f -S0 3 NR»-, -CSS-, -SCS-, -(N0)R»-, -(P0)R*-, -NR«C00-, -NR'SO,-, -0-, -NR 4 -, -5-, -SO- and -SO,- (R* and R 5 being independently selected from the group consisting of hydrogen and lower alkyl; and R* being selected from the group consisting of hydrogen, nitrile and nitro) ; and G is either a moiety which together with L forms a heterocyclic ring having at least one nitrogen atom or is selected from the group consist¬ ing of hydrogen, lower alkyl, lower alkenyl, lover alkynyl, (C 3 -C 7 )cyclo- alkyl, bromo(lover)alkyl, chloro(lower) lkyl, fluoro(lower)alkyl, cyano- (lower)alkyl, carboxy(lower)alkyl, (lover)alkoxycarbonyl(lower)alkyl, ,C t -C l 0 ) iτγl , (C τ -C li )arylalkyl, di(lower)alkylamino(lower)alkyl, fluoro- substituted analogs of the foregoing and a moiety which together with L forms a heterocyclic ring having at least one nitrogen atom; Said method of treatment further comprising the step of inhibiting sex steroid formation by administering therapeutically effective amount of at least one sex steroid formation inhibitor. 2. The method of Claim 1 wherein said inhibition of sex steroid synthesis includes administering a therapeutically effective amount of an inhibitor of 5α-reductase. 3. The method of Claim 1 wherein said inhibition of sex steroid synthesis includes administering a therapeutically effective amount of an inhibitor of 17β-hydro^steroid dehydrogenase. 4. The method of Claim 1 wherein said inhibition of sex steroid synthesis includes administering a therapeutically effective amount of an inhibitor of 5α-reductase and an inhibitor of 17β-hydroχysteroid dehydrogenase. SUBSTITUTE SHEET 5. The method according to Claim 1 further comprising the step of administering a therapeutically effective amount of an antiestrogen. 6. The method according to Claim 2 further comprising the step of administering a therapeutically effective amount of an antiestrogen. 7. The method according to Claim 3 further comprising the step of administering a therapeutically effective amount of an antiestrogen. 8. The method according to Claim 4 further comprising the step of administering a therapeutically effective amount of an antiestrogen. 9. The method of Claim 1 wherein said inhibition includes. he step of admin stering a mixture of sex steroid inhibitors which together are capable of inhibition the function of 5α-reductase and the function of 17β-hydroxysteroid dehydrogenase and the function of 3β-hydroxysteroid dehydrogenase. 10. The method according to Claim 9 further comprising the step of administering a therapeutically effective amount of an antiestrogen. 11. The method of Claim 1 further comprising the step of inhibiting testicular hormonal secretion of said warm-blooded animal. 12. The method of Claim 11 wherein said testicular hormonal secretion is inhibited by at least one technique selected from the group consisting of surgical castration, administration of an antagonist of luteinizing hormone releasing hormone, and administration of an agonist of luteinizing hormone releasing hormone. * 13. The method of Claim 1 wherein said inhibition of sex steroid synthesis includes the step of administering an inhibitor of 5o-reductase activity, and wherein said method further includes inhibiting the testi¬ cular hormonal secretion of said warm-blooded animal. 14. The method of Claim 2 which includes inhibiting testicular hormone secretion of said warm-blooded animal. 15. The method of Claim 3 which includes inhibiting testicular hormone secretion of said warm-blooded animal. 16. The method of Claim 4 which includes inhibiting testicular hormone secretion of said warm-blooded animal. 17. The method of Claim 5 which includes inhibiting testicular hormone secretion of said warm-blooded animal. 18. The method of Claim 6 which includes inhibiting testicular hormone secretion of said warm-blooded animal. 19. The method of Claim 7 which includes inhibiting testicular hormone secretion of said warm-blooded animal. 20. The method of Claim 8 which includes inhibiting testicular hormone secretion of said warm-blooded animal. SUBSTITUTE SHEET 56 21. The method of Claim 9 which includes inhibiting testicular hormone secretion of said warm-blooded animal. 22. The method of Claim 10 which includes inhibiting testicular hormone secretion of said warm-blooded animal. 23. The method of Claim 1 wherein said inhibitor of sex steroid formation is selected from the group consisting of: N-butyl, N-methyl-11-(16'o-chloro-3' ,17'β-dihydroxy estra-1» ,3' ,5' (10')- trien-7'α-yl) undecanamide ("EM 139"). N-n-butyl-N-methyl-ll-de'o-chloro-S ' ,17'α-dihydroxy-estra-l' ,3 ' ,5 ' (10' )- trien-7 'a-yl) undecanamide ("EM 170") N-n-butyl-N-methyl-ll-(16'o-bromo-3 ' , 17 'α-dihydroxy-estra-l ' ,3 ' ,5 ' (10' ) - trien-7 'α-yl) undecanamide ("EM 171") 57 24. The method of Claim 1 wherein said antiandrogen is represented by the formula: B 17 -* wherein the dotted line represents an optional double bond; x is 0, R is [-CH,-] (with y being an integer from 4 to 20), R 1T is hydrogen, (B) lower alkyl or a moiety which together with R 1T forms: wherein R 1 T ( 8 μ ) is selected from the group consisting of hydrogen, ( a . hydroxyl, lower alkyl, acyloxy, and a moiety which, together with R iT forms; SUBSTITUTE SHEET 25. The method of Claim 1 wherein said antiandrogen is represented by the general formula: wherein the dotted lines represent optional double bonds; wherein R lβ is hydrogen or lower alkyl, R 11 is absent, hydrogen or methyl in β position. .x f Cα) is selected from the group consisting of hydrogen, hydroxyl, lover alkanoyloxy, lover alkyl, lover alkenyl, lover alkynyl, halo(lower)alkyl, halo(lower)alkenyl, halo(lower)alkynyl and fluoro- substituted aromatic ring, and a moiety which, together with R lτ ^ forms (8) R I » p is selected from the group consisting of hydroxyl, (C t -C 3 β ) alkanoyloxy, (C 3 -C 7 ) alkanoyloxy , (C,-C r )alkynoyloxy, aroyloxy, alkanoylo¬ xy, cycloalkenyloxy, 1-alkyloxy-alkyloxy, 1-alkyloxycycloalkyloχy, alkyl- silyloxy, carboxyl, alkanoyl and a moiety which together with R 17 forms 26. The method of Claim 1 wherein said antiandrogen is represented by the general formula: wherein the AB-ring junction is trans, the dotted lines represent option¬ al pi bonds; wherein y is an integer from 4 to 20, wherein L is selected from the group consisting of -C0NR*-, -CSNR*-, -NR , C0-, -NR*CS- and -CH S - (R* and R 1 being hydrogen or methyl) and G is selected from the group consisting of n-propyl, n-butyl, n-pentyl and haloalkyl. 27. A method for treatment of prostate cancer in a human or other warm-blooded animal in need of such treatment. Said method comprising the steps of inhibiting the sex steroid formation by administering a therapeutically effect of amount of an inhibitor of sex steroid formation SUBSTITUTE SHEET having, as part of the molecular structure, a sex-steroid nucleus and, as another part of its molecular structure, at least one side chain repre¬ sented by the formula: -R 1 C-B-R*-] L-G wherein: x is an integer from 0 to 6, wherein at least one of L and G is a polar moiety distanced from said ring carbon by at least three interven¬ ing atoms, and wherein: R 1 and R 3 are independently either absent or selected from the group consisting of straight- or branched-chain alkylene, straight- or branched chain alkynylene, straight- or branched-chain alkenylene, phenylene and fluoro-substituted analogs of the foregoing; B is either absent or selected from the group consisting of -0-, -S-, -Se-, -SO-, -S0 3 -, -NR**-, -SiR» 3 -, -CR'OR 1 -, -NR»C0-, -NR»CS-, -C0NR'-, -CSNR 1 -, -C00-, -COS-, -SCO-, -CSS-, -SCS-, -OCO- and phenylene (R 1 being hydrogen or lover alkyl) ; L is either a moiety which together with G, forms a heterocyclic ring having at least one nitrogen atom or is selected from the group consisting of lover alkyl, -C0NR*-, -CSNR*-, -NR«C0-, -NR'CS-, -NR'CONR*- NR« -NR*C-NR*-, -S0 3 NR»-, -CSS-, -SCS-, -(N0)R*-, -(P0)R*-, -NR'COO-, -NR»S0 3 -, -0-, -NR*-, -S-, -SO- and -S0 3 - (R* and R* being independently selected from the group consisting of hydrogen and lover alkyl; and R* being selected from the group consisting of hydrogen, nitrile and nitro) ; and G is selected from the group consisting of hydrogen, lover alkyl, lower alkenyl, lower alkynyl, (C 3 -C 7 )cycloalkyl, bromo(lower)alkyl, chloro(lower)alkyl, fluoro(lower)alkyl, cyano(lower)alkyl, carbcxy- (lower)alkyl, (lover)alkoxycarbonyl(lover)alkyl, (C,-C 10 )aryl, (C T -C 1X )- arylalkyl, didower)alkylaraino(lower)alkyl, fluoro-substituted analogs of the foregoing and a moiety which together with L forms a heterocyclic ring having at least one nitrogen atom; said method of treating prostate cancer further comprising the step of administering a therapeutically effective amount of an antiandrogen) 28. The method according to Claim 27 wherein the same method includes the step of administering a therapeutically effective amount of an inhibitor of 5α-reductase 29. The method of Claim 27 wherein said inhibition of sex steroid synthesis includes administering a therapeutically effective amount of an inhibitor of 17β-hydroxysteroid dehydrogenase. 30. The method of Claim 27 wherein said inhibition of sex steroid synthesis includes administering a therapeutically effective amount of an inhibitor of 5α-reductase and an inhibitor of 17β-hydroxysteroid dehydro¬ genase. 31. The method according to Claim 27 further comprising the step of administering a therapeutically effective amount of an antiestrogen. 32. The method according to Claim 28 further comprising the step of administering a therapeutically effective amount of an antiestrogen. 33. The method according to Claim 29 further comprising the step of administering a therapeutically effective amount of an antiestrogen. SUBSTITUTE SHEET 34. The method according to Claim 30 further comprising the step of administering a therapeutically effective amount of an antiestrogen. 35. The method Of Claim 27 wherein said inhibition includes the step of administering a mixture of sex steroid inhibitors which together are capable of inhibition the function of 5α-reductase and the function of 17β-hydroxysteroid dehydrogenase and the function of 3β-hydroxysteroid dehydrogenase. 36. The method according to Claim 35 further comprising the step of administering a therapeutically effective amount of an antiestrogen. 37. The method of Claim 27 further comprising the step of inhibiting testicular hormonal secretion of said warm-blooded animal. 38. The method of Claim 37 wherein said testicular hormonal secretion is inhibited by at least one technique selected from the group consisting of surgical castration, administration of an antagonist of luteinizing hormone releasing hormone, and administration of an agonist of luteinizing hormone releasing hormone. 39. The method of Claim 27 vherein said inhibition of sex steroid synthesis includes the step of administering an inhibitor of 5α-reductase activity, and wherein said method further includes inhibiting the testi¬ cular hormonal secretion of said warm-blooded animal. 40. The method of Claim 28 which includes inhibiting the testicular hormonal secretion of said warm-blooded animal. 41. The method of Claim 29 which includes inhibiting the testicular hormonal secretion of said warm-blooded animal. 42. The method of Claim 30 which includes inhibiting the testicular hormonal secretion of said warm-blooded animal. 43. The method of Claim 31 which includes inhibiting the testicular hormonal secretion of said warm-blooded animal. 44. The method of Claim 32 which includes inhibiting the testicular hormonal secretion of said warm-blooded animal. 45. The method of Claim 33 which includes inhibiting the testicular hormonal secretion of said warm-blooded animal. 46. The method of Claim 34 which includes inhibiting the testicular hormonal secretion of said warm-blooded animal. 47. The method of Claim 35 which includes inhibiting the testicular hormonal secretion of said warm-blooded animal. 48. The method of Claim 36 which includes inhibiting the testicular hormonal secretion of said warm-blooded animal. 49. -The method of Claim 27 wherein said inhibitor of sex steroid formation is selected from the group consisting of: ITUTE SHEET N-butyl , N-methyl-11- ( 16 ' α-chloro-3 * , 17 ' β-dihydroxy estra-1 ' , 3 ' , 5 • ( 10 ' ) ■ trien-7 'α-yl) undecanamide ("EM 139") . N-n-butyl-N-methyl-ll-(16'α-chloro-3 ' ,17'α-dihydroxy-estra-l' ,3 ' , 5 ' (10' )- trien-7 'o-yl) undecanamide ("EM 170") N-n-butyl-N-oethyl-ll-(16'o-bromo-3' ,17'o-dihydroxy-estra-l* ,3',5'(10')- trien-7'o-yl) undecanamide ("EM 171") 50. The method of Claim 27 wherein said antiandrogen is represented by the formula: R - f fi wherein the dotted line represents an optional double bond; x is 0, R 1 is (a.) [-CH 3 -] (with y being an integer from 4 to 20), R 1T is hydrogen, lower alkyl or a moiety which together with R 1T ^ forms: wherein R lτ p is selected from the group consisting of hydrogen, hydroxyl, lover alkyl, acyloxy, and a moiety vhich, together with R 1T forms: SUBSTITUTE SHEET 51. The method of Claim 27 wherein said antiandrogen is represented by the general formula: wherein the dotted lines represent optional double bonds; wherein R lβ is hydrogen or lower alkyl, R 13 is absent, hydrogen or methyl in β position, R 1T is selected from the group consisting of hydrogen, hydroxyl, lower alkanoyloxy, lover alkyl, lover alkenyl, lover alkynyl, halo(lower)alkyl, halo(lower)alkenyl, halo(lover)alkynyl and fluoro- substituted aromatic ring, and a moiety vhich, together vith R 1 ' ' forms (B) R 1T is selected from the group consisting of hydroxyl, (C 3 -C 39 ) alkanoyloxy, (C 3 -C 7 )alkenoyloxy, (C 3 -C τ )alkynoylosy, aroyloxy, alkanoylo¬ xy, cycloalkenyloxy, 1-alkyloxy-alkylojqr, 1-alkyloxycycloalkylcoqr. alkyl- silyloxy, carboxyl, alkanoyl and a moiety which together with R 1T forms 52. The method of Claim 27 wherein said antiandrogen is represented by the general formula: wherein the AB-ring junction is trans, the dotted lines represent option¬ al pi bonds; wherein y is an integer from 4 to 20, wherein L is selected from the group consisting of -C0NR*-, -CSNR*-, -NR»CO-, -NR»CS- and -CR-- (R* and R'being hydrogen or methyl) and G is selected from the group consisting of n-propyl, n-butyl, n-pβntyl and haloalkyl. 53. The method of Claim 27 wherein the molecular structure of said anti¬ androgen is an androgen nucleus substitute data ring carbon with at least one side chain represented by the formula -R 1 E-B-R 1 -] ? L-G. 54. The method of Claim 27 wherein said inhibitor of sex steroid forma¬ tion has, as part of its molecular structure, a substituted or unsubsti¬ tuted estrogen nucleus zeneral structure I wherein the dotted lines represent optional pi bonds and wherein said compound includes as another part of its molecular structure at least one side * chain ET substitueiϊted onto a ring carbon of said general structure I represented by the formula -R 1 [-B-R 2 -] L-G wherein at least one of said side chains is substituted at a ring carbon selected from the group consisting of carbon 14, carbon 15, carbon 16 and carbon 17, wherein: x is an integer from 0 to 6, wherein at least one of L and G is a polar moiety distanced from said ring carbon by at least three interven¬ ing atoms, and wherein: R 1 and R* are independently either absent or selected from the group consisting of straight- or branched-chain alkylene, straight- or branch¬ ed-chain alkynylene, straight- or branched-chain alkenylene, phenylene, and fluoro-substituted analogs of the foregoing; B is either absent or selected from the group consisting of -0-, -S-, -Se-, -SO-, -SO,-, -NR»-, -SiR 1 ,-, -CR»OR»-, -NR'CO-, -NR*CS-, -CQHR*-, -CSNR 1 -, -C00-, -COS-, -SCO-, -CSS-, -SCS-, -OCC- and phenylene (R 1 being hydrogen or lover alkyl) ; L is either a moiety which together with G, forms a heterocyclic ring having at least one nitrogen atom or is selected from the group consisting of lover alkyl, -C0HR*-, -CSNR*-, -NR«C0-, -NR'CS-, -NR'CONR*- NR« -HR*C-NR»-, -S0 3 NR*-, -CSS-, -SCS-, -(N0)R»-, -(P0)R»-, -NR'COO-, -HR«S0 3 -, -0-, -NR*-, -S-, -SO- and -S0 3 - (R» and R» being independently selected from the group consisting of hydrogen and lover alkyl; and R« being selected from the group consisting of hydrogen, nitrile and nitro) ; and G is either a moiety vhich together with L forms a heterocyclic ring having at least one nitrogen atom or is selected from the group consist¬ ing of hydrogen, lower alkyl, lower alkenyl, lover alkynyl, (C j -C 7 )cyclo- alkyl, bromo(lower)alkyl, chloro(lower)alkyl, fluoro(lower)alkyl, iodo- (lower)alkyl, cyano(lower)alkyl, carboxy(lower)alkyl, (lower)alkoxycarbo- nyl(lower)alkyl, (C,-C 1e )aryl, (C,-C 13 )arylalkyl, di(lower)alkylamino- (lower)alkyl, fluoro-substituted analogs of the foregoing. 55. The method of Claim 27 wherein said inhibitor of sex steroid formation has, as part of its molecular structure, a substituted or unsusbstituted estrogen nucleus of general structure I. wherein the dotted lines represent optional pi bonds; and wherein said compound includes, as another part of its molecular structure, at least one substitution of a side chain represented by the formula -R 1 [-B-R 1 } L-G onto a ring carbon of said general structure I in at least one position selected from the group consisting of 7, 14, 15, 16 and 17, wherein said general structure I further includes at least one substitution selected from the group consisting of 15-halo, 16-halo, a 15,16 bridge atom (preferably carbon), a 14,15 bridge atom (preferably oxygen), 16-pi-bondβd lover alkyl. 56. The method of Claim 27 wherein said antiandrogen is represented by the formula: wherein the dotted line represents an optional double bond; x is 0, R 1 is (a.) [-CH j -] (with y being an integer from 44 ttoo 20), R 1T is hydrogen, lower alkyl or a moiety which together with R" ^ forms: (B) wherein R 1T μ is selected from the group consisting of hydrogen, hydroxyl, lover alkyl, acyloxy, and a moiety which, together with R 1T forms: SUBSTITUTE SHEET 57. The method of Claim 27 wherein said antiandrogen is represented by the general formula: wherein the dotted lines represent optional double bonds; wherein R 10 is hydrogen or lower alkyl, R 1J is absent, hydrogen or methyl in β position, R 1T is selected from the group consisting of hydrogen, hydroxyl, lower alkanoyloxy, lower alkyl, lower alkenyl, lower alkynyl, halo(lower)alkyl, halo(lower)alkenyl, halo(lower)alkynyl and fluoro- substituted aromatic ring, and a moiety which, together with R 17 " forms (S) R 1T F is selected from the group consisting of hydroxyl, (C 1 -C 3e ) alkanoyloxy, (C j -C 7 )alkenoyloxy, (C 3 -C 7 )alkynoyloxy, aroyloxy, alkenoylo- xy, cycloalkenyloxy, 1-alkyloxy-alkyloxy, 1-alkyloxycycloalkyloxy, alkyl- STITUTE SHEET 12 silyloxy, carboxyl, alkanoyl and a moiety which together with R 17 forms 58. The method of Claim 27 wherein said antiandrogen is represented by the general formula: wherein the AB-ring junction is trans, the dotted lines represent al pi gonds; wherein y is an integer from 4 to 20, wherein L is se from the group consisting of -CQHR*-, -CSNR*-, -NR«CO-, -NR«CS- an (R* and R*being hydrogen or methyl) and G is selected from the gro consisting of n-propyl, n-butyl, n-pentyl and haloalkyl. 59. A method for treating prostate cancer in a human or other warm-blooded animal in need of such treatment, said method including the steps of administering a therapeutically effective amount of an inhibitor of 5o-reductase activity and administering a therapeutically effective amount of an antiandrogen. 6 0 The method of Claim 59 further comprising administering a therapeutically effective amount of at least one compound selected from the group consisting of an antiestrogen, an inhibitor of aromatase activity, an inhibitor of 178-hydroxysteroid dehydrogenase activity, and inhibitor of testicular hormonal secretion. 61. The method of Claim 59 where testicular hormone secretion is blocked by surgical castration. 62. The method of Claim 55 wherein said side chain is substituted onto said estrogen nucleus in a position selected from the group consisting of 7a, 15 and 17α. 63. A method for treating prostate cancer in a human or other warm-blood¬ ed animal in need of such treatment, said method including the steps of administering a therapeutically effective amount of an inhibitor of 17β- HSD and administering a therapeutically effective amount of an antiandro¬ gen.. SUBSTITUTE SHEET 64. A method of Claim 63 further comprising administering a therapeutic¬ ally effective amount of at least one compound selected from the group consisting of an antiestrogen, an inhibitor of 5o-reductase activity, an LHRH agonist and an LHRH antagonist. 65. The method of Claim 63 where testicular hormone secretion is blocked by surgical castration. 66. The method of Claim 64 where testicular hormone secretion is blocked by surgical castration. 67. A method for treating prostate cancer in a human or other warm-blood¬ ed animal in need of such treatment, said method including the steps of admin stering an effective amount of an antiandrogen and at least one compound selected from the groups consisting of inhibitors of extragona- dal and extraadrenal sex steroid formation. 58. The method of Claim 67 where testicular steroid secretion is blocked by surgical castration. 69. The method of Claim 67 where serum said inhibition of sex steroid synthesis includes administering a therapeutically effective amount of an inhibitor of 5o-reductase. 70. The method of Claim 67 where serum said inhibition of sex steroid synthesis includes administering a therapeutially effective amount of an inhibitor of 17β-hydroxysteroid dehydrogenase. 71. The method of Claim 67 wherein said inhibition of sex steroid synthesis includes administering a therapeutically effective amount of an inhibitor of 5α-reductase and an inhibitor of 17β-hydroxysteroid dehydro¬ genase. 72. The method according to Claim 67 further comprising the step of administering a therapeutically effective amount of an antiestrogen. SHEET 73. The method according to Claim 69 further comprising the step of administering a therapeutically effective amount of an antiestrogen. 74. The method according to Claim 70 further comprising the step of administering a therapeutically effective amount of an antiestrogen. 75. The method according to Claim 71 further comprising the step of administering a therapeutically effective amount of an antiestrogen. 76. The method of Claim 67 further comprising the step of inhibiting testicular hormonal secretion of said warm-blooded animal. 77. The method of Claim 76 wherein said testicular hormonal secretion is inhibited by at least one technique selected from the group consistin ,of surgical castration, administration of an antagonist of luteinizing hormone releasing hormone, and administration of an agonist of luteinizing hormone releasing hormone. 78. The method of Claim 67 wherein said inhibition of sex steroid synthesis includes the step of administering an inhibitor of 5α-reductase activity, and wherein said method further includes inhibiting the testi¬ cular hormonal secretion of said warm-blooded animal. 79. The method of Claim 69 which includes inhibiting testicular hormone secretion of said warm-blooded animal. 80. The method of Claim 70 which includes inhibiting testicular hormone secretion of said warm-blooded animal. 81. The method of Claim 71 which includes inhibiting testicular hormone secretion of said warm-blooded animal. 82. The method of Claim 72 which includes inhibiting testicular hormone secretion of said warm-blooded animal. 83. The method of Claim 73 which includes inhibiting testicular hormone secretion of said warm-blooded animal. 84. The method of Claim 74 which includes inhibiting testicular hormone secretion of said warm-blooded animal. 85. The method of Claim 75 which includes inhibiting testicular hormone secretion of said warm-blooded animal. 86. A kit for treating prostate cancer, said kit including a plurality of separate containers, each containing at least one active ingredient useful in a combination therapy for treatment of prostate cancer (with or without additional pharmaceutical carrier or diluent) and each container containing at least one active ingredient which is not contained in any other container ia said kit, wherein one of said containers contains an antiandrogen and another of said containers contains an active ingredient selected from the group consisting of an inhibitor of 5α-reductase activity and an inhibitor capable of blocking formation of natural sex steroids from dehydroepiandrosterone and from 4-androstenedione in peripheral tissues. 87. The kit of Claim 86 wherein said kit further comprises at least one separate container containing an active ingredient selected from the group consisting of an inhibitor of testicular hormonal secretion, an inhibitor of aromatase, an inhibitor of 17β-hydroxysteroid dehydrogenase and an inhibitor of 3β-hydroxysteroid dehydrogenase. 88. A kit for treating prostate cancer, said kit including a plurality of separate containers, each containing at least one active ingredient useful in a combination therapy for treatment of prostate cancer (with or without additional pharmaceutical carrier or diluent) and each container containing at least one active ingredient vhich is not contained in any other container in said kit, wherein one of said containers contains an inhibitor of sex steroid formation and another of said containers contains (with or without carrier or diluent) an antiandrogen having, as part of its molecular structure, a substituted or unsubs¬ tituted androgenic nucleus of the formula: and having as another part of its molecular structure, at least one side chain represented by the formula: -R 1 [-B-R J -] L-G said chain being substituted onto said androgenic nucleus at a position selected from the group consisting of 6, 7, 14, 15, 16 and 17, wherein: x is an integer from 0 to 6, wherein at least one of L and G is a polar moiety distanced from said ring carbon by at least three interven¬ ing atoms, and wherein: R 1 and R 3 are independently either absent or selected from the group consisting of straight- or branched-chain alkylene, straight- or branched chain alkynylene, straight- or branched-chain alkenylene, phenylene and fluoro-substituted analogs of the foregoing; B is either absent or selected from the group consisting of -0-, -S-, -Se-, -SO-, -SO,-, -NR 1 -, -SiR 1 ,-, -CR-OR 1 -, -NR>C0-, -NR»CS-, -CONR**-, -CSNR 1 -, -C00-, -COS-, -SCO-, -CSS-, -SCS-, -OC0- and phenylene (R 1 being hydrogen or lower alkyl) ; L is either a moiety which together with G, forms a heterocyclic ring having at least one nitrogen atom or is selected from the group consisting of lower alkyl, -CONR*-, -CSNR*-, -NR*C0-, -HR*CS-, -NR*C0NR*- NR« |l -NR»C-NR*-, -S0 3 NR 4 -, -CSS-, -SCS-, -(NO)R*-, -(P0)R*-, -NR*C00-, -NR«S0 j -, -0-, -NR*-, -S-, -SO- and -S0 3 - (R* and R s being independently selected from the group consisting of hydrogen and lower alkyl; and R* being selected from the group consisting of hydrogen, nitrile and nitro) ; and G is either a moiety which together with L forms a heterocyclic ring having at least one nitrogen atom or is selected from the group consist¬ ing of hydrogen, lower alkyl, lover alkenyl, lover alkynyl, (C 3 -C 7 )cyclo- alkyl, bromo(lover)alkyl, chloro(lover)alkyl, fluoro(lover)alkyl, cyano- (lover)alkyl, carboxy(lover)alkyl, (lower)alkoxycarbonyl(lower)alkyl, (C,-C lβ )aryl, (C -C 11 )arylallqrl, di(lower)alkylamino(lower)alkyl, fluoro- substituted analogs of the foregoing and a moiety vhich together with L forms a heterocyclic ring having at least one nitrogen atom; 89. The kit of Claim 88 wherein said kit further comprises at least one separate container containing an active ingredient selected from the group consisting of an inhibitor of testicular hormonal secretion, an inhibitor of aromatase, an inhibitor of 17β-hydroxysteroid dehydrogenase and an inhibitor of 3β-hydroxysteroid dehydrogenase. 90. A phamaceutical composition for treatment of prostate cancer comprising an antiandrogen (with or without a pharmaceutical diluent or carrier) and at least one active ingredient selected from the group consisting of an inhibitor of 5α-reductase activity and an inhibitor capable of blocking formation of natural sex steroids from dehydroepiandrosterone and from 4-androstenedione in peripheral tissues. 91. The pharmaceutical composition of Claim 90 further comprising at least one active ingredient selected from the group consisting of an inhibitor of testicular hormonal secretions, an inhibitor of aromatase, an inhibitor of 17β-hydroxysteroid dehydrogenase and an inhibitor of β-hydroxysteroid dehydrogenase. 92. A pharmaceutical composition for treatment of prostate cancer comprising an inhibitor of sex steroid formation,and an antiandrogen having, as part of its molecular structure, a substituted or unsubs¬ tituted androgenic nucleus of the formula: and having as another part of its molecular structure at least cne side chain represented by the formula: -R 1 [-B-R 2 -] L-G said chain being substituted onto said androgenic nucleus at a position selected from the group consisting of 6, 7, 14, 15, 16 and 17, wherein: x is an integer from 0 to 6, wherein at least one of L and G is a polar moiety distanced from said ring carbon by at least three interven¬ ing atoms, and wherein: -_ R 1 and R 3 are independently either absent or selected from the group consisting of straight- or branched-chain alkylene, straight- or branched chain alkynylene, straight- or branched-chain alkenylene, phenylene and fluoro-substituted analogs of the foregoing; B is either absent or selected from the group consisting of -0-, -S-, -Se-, -SO-, -S0 3 -, -NR»-, -SiR» 3 -, -CR»0R»-. -NR s C0-, -NR'CS-, -CONR 1 -, -CSNR 1 -, -C00-, -COS-, -SCO-, -CSS-, -SCS-, -OCO- and phenylene (R 1 being hydrogen or lower alkyl) ; L is either a moiety which together with G, forms a heterocyclic ring having at least one nitrogen atom or is selected from the group consisting of lower alkyl, -CQNR*-, -CSNR*-, -NR'CO-, -NR'CS-, -NR'CONR*- NR« -NR«C-NR*-, -S0 3 NR*-, -CSS-, -SCS-, -(NO)R»-, -(P0)R*-, -NR«C00-, -NR»S0 3 -, -0-, -NR*-, -S-, -SO- and -S0 3 - (R* and R* being independently selected from the group consisting of hydrogen and lower alkyl; and R' being selected from the group consisting of hydrogen, nitrile and nitro) ; and EET G is either a moiety which together with L forms a heterocyclic ring having at least one nitrogen atom or is selected from the group consist¬ ing of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (C 3 -C τ )cyclo- alkyl, bromo(lower)alkyl, chloro(lower)alkyl, fluoro(lower)alkyl, cyano- (lower)alkyl, carboxy(lower)alkyl, (lower)alkoxycarbony1(lower)alkyl, (C,-C lβ )aryl, (C 7 -C 13 )arylalkyl, di(lower)alkylamino(lower)alkyl, fluoro- substituted analogs of the foregoing and a moiety which together with L forms a heterocyclic ring having at least one nitrogen atom. 93. The pharmaceutical composition of Claim 92 wherein said composition further comprises at least one active ingredient selected from the group consisting of an inhibitor of testicular hormonal secretions, an inhibitor of aromatase activity an inhibitor of 17β-hydroxysteroid dehydrogenase and an inhibitor of 3β-hydroxysteroid dehydrogenase. 94. The method of claim 27 wherein said antiandrogen is selected from the group consisting of Flutamide , Anandron , Casodex and Androcur . 95. A merhod for treatment of prostate cancer in a human or other warm-blooded animal in need of such treatment. Said mer.hod comprising ' the steps of inhibiting the sex steroid formation by administering a therapeutically effect of amount of an inhibitor of sex steroid forπation having, as part of the molecular structure, a sex-steroid nucleus and, as another part of its molecular structure, at least one side chain repre¬ sented by the formul : -RH-B-R»-] χ L-G vhβrein: x is an integer from 0 to 6, vhβrein at least one of L and G is a polar moiety distanced from said ring carbon by at least three interven¬ ing atoms, and wherein: R 1 and R* are independently either absent or selected from the group consisting of straight- or branched-chain alkylene, straight- or branched chain alkynylene, straight- or branched-chain alkenylene, phenylene and fluoro-substituted analogs of the foregoing; B is either absent or selected from the group consisting of -0-, -S-, -Se-, -SO-, -S0 3 -, -NR»-, -SiR 1 ,-, -CR»OR»-, -NR'CO-, -NR'CS-, -C0NR 3 -, -CSSR'-, -C00-, -COS-, -SCO-, -CSS-, -SCS-, -OCO- and phenylene (R 3 being hydrogen or lover alkyl) ; L is either a moiety vhich together with G, foms a heterocyclic ring having at least one nitrogen atom or is selected from the group consisting of lover alkyl, -C0NR*- , -CSUR*-, -NR*C0-, -_m »u_>- , -«Λ-IΛMIΛ— NR « -HR«C-HR*- , -S0 3 NR*-, -CSS-, -SCS- , -(NO)R*-, -(PO)R*-, -NR'COO-, -NR'SO j -, -0- , -NR*- , -S-, -SO- and -S0 3 - (R* and R 5 being independently selected from the group consisting of hydrogen and lover alkyl ; and R* being selected from the group consisting of hydrogen, nitrile and nitro) ; and G is selected from the group consisting of hydrogen, lover alkyl, lover alkenyl , lover alkynyi, (Cj-c ) cycloalkyl, bromo (lower) alkyl, chloro (lover) alkyl , fluoro (lover) alkyl , cyano (lover) alkyl , carboxy- ( lover) alkyl , ( lover ) alkoxycarbonyl ( lover) alkyl , (C,-C 10 ) aryl , (C 7 -C l l ) - arylalkyl , di(lover)alkylamino(lover)al yl, fluoro-substituted analogs of the foregoing and a moiety vhich together vith forms a heterocyclic ring having at least one nitrogen atom; said method of treating prostate cancer further comprising the step of administering a therapeutically effective amount of an inhibitor of 5α-reductase. 96. A method for treating prostate cancer in a human or other warm-blooded animal in need of such treatment , said method comprising the steps of inhibiting testicular hormonal secretion of said warm ¬ blooded animal , and administering a pharmaceutically effective amount of a 5o reductase inhibitor. SUBSTITUTE SHEET 97. The method of claim 96 wherein said method further comprises the step of administering a pharmaceutically effective amount of at least one compound selected from the group consisting of an antiestrogen, an inhibitor of 178-hydroxysteroid dehydrogenase and an inhibitor of aromatase activity. 98. A method for treating prostate cancer in a human or other warm-blooded animal in need of such treatment, said method including the steps of inhibiting testicular hormonal secretion of said warm¬ blooded animal, and administering a pharmaceutically effective amount of an antiestrogen. 99. The method of claim 98 wherein said method further comprises the step of administering a pharmaceutically effective amount of an antiandrogen. 100. The method of claim 98 wherein said method further comprises the step of administering an effective amount of a 5α-reductase inhibitor. 101. The method of claim 100 wherein said 5α-reductase inhibitor is Proscar. 102. The method of claim 98 wherein said testicular hormonal secretion is inhibited by at least one technique selected from the group consisting of surgical castration, administration of an antagonist of luteinizing hormone releasing hormone, and administration of an agonist of luteinizing hormone releasing hormone. 103. A method for treating prostate cancer in a human or other warm-blooded animal in need of such treatment, said method including the steps of administering a pharmaceutically effective amount of an antiestrogen in combination with a pharmaceutically effective amount of at least one compound selected from the group consisting of an antiandrogen, a 5 -reductase inhibitor and a sex steroid inhibitor. 104. The method of claim 2, wherein said inhibitor of 5α-reductase is Proscar. 105. The method of claim 28, wherein said inhibitor of 5α-reductase is Proscar. TE SHEET 106. The method of claim 1 wherein said inhibitor of sex steroid formation is: wherein R is either hydrogen or ethynyl. 107. The method of claim 27 wherein said inhibitor of sex steroid formation is: wherein R is either hydrogen or ethynyl.

Inventors: LABRIE FERNAND, LABRIE, FERNAND
Applicants: ENDORECHERCHE INC, ENDORECHERCHE INC.
Application year: 1990
Main classification: A61K31
IPC codes: A61K31, A61P35, A61P43, C07J1, C07J17, C07J41