| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | April 2, 2002 |
| PATENT TITLE |
4-aza steroids |
| PATENT ABSTRACT | The invention related to 4-aza-17.beta.-(cyclopropoxy)-androst-5.alpha.-androstan-3-one, 4-aza-17.beta.-(cyclopropylamino)-androst-4-en-3-one and related compounds and to compositions incorporating these compounds, as well as the inhibition of C.sub.17-20 lyase, 5.alpha.-reductase and C.sub.17.alpha. -hydroxylase and to the use of these compounds in the treatment of androgen and estrogen mediated disorders, including benign prostatic hyperplasia, androgen mediated prostate cancer, estrogen mediated breast cancer and to DHT-mediated disorders such as acne. Disorders relating to the oversynthesis of cortisol, for example, Cushing's Syndrome, are also included. The treatment of androgen-dependent disorders also includes a combination therapy with known androgen-receptor antagonists, such as flutamide. The compounds of the invention have the following general formula: ##STR1## |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | February 11, 1997 |
| PATENT REFERENCES CITED |
Bhattacharya et al, Silyation-Mediated Oxidation of 4-Aza-3-ketosteroids with DDQ Proceeds via DDQ-Substrate Adducts, J. Am. chem. Soc. 110:3318-3319, (1988). Milewich et al, 17.beta.-Hydroxy-5-Oxo-3,5-seco-4-Norandrostane-3-Carboxylic Acid, Organic Syntheses vol. 6, 690-691, 1988. Bohlmann, A New Route to Seroidal Vinyl Fluorides, Tetrahedron Ltrs, 35 (1):85-88, (1994). Klinik et al., Steroid biosynthesis inhibitors of Cushing's syndrome, Clin. Investig., 72:481-488 (1994). Raamunson, et al., Azasteroids: Structure-Activity Relationships for Inhibition of 5.alpha.-Reductase and of Androgen Receptor Binding, J. Med. Chem., 29:2296-2315 (1986). Xun et al., J. Med. Chem., 38, 1158-1173 (1995). |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A compound, or a pharmaceutically acceptable salt thereof having the following formula: ##STR42## wherein: A is O or NH; R.sup.1 is H or C.sub.1-4 alkyl; R.sup.2 is H, halo, phenylthio, phenylsulfinyl or phenylsulfonyl; R.sup.3 is H, halo, C.sub.1-4 alkylthio, C.sub.1-4 alkylsulfinyl or C.sub.1-4 alkylsulfonyl; R.sup.4 is H, C.sub.1-4 alkyl or C.sub.2-4 alkenyl; R.sup.5 is H or C.sub.1-4 alkyl; Z is: (a) oxo; or (b) (H) (H) or an .alpha.-hydrogen and .beta.-substituent selected from the group consisting of: C.sub.1-4 alkyl, C.sub.2-4 alkenyl, hydroxy, C.sub.1-4 alkanoyloxy, C.sub.1-4 alkoxycarbonylmethyl, carboxymethyl, C.sub.1-4 alkoxycarbonyl, carboxy, C.sub.1-4 alkanoyl and halo; with the proviso that when: (a) R.sup.2 is present and is other than hydrogen, a 1,2 double bond is present, or (b) Z is oxo, a 6,7 double bond is not present, or (c) R.sup.1 is H or C .sub.1-4 alkyl, and R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are H, and Z is (H)(H), and no double bonds exist in any of the positions 1(2), 5(6) or 6(7), A is not NH, or (d) A is O, and Z is (H)(H), and R.sup.2, R.sup.3,R.sup.4 and R.sup.5 are H, R.sup.1 is C.sub.3-4 alkyl. 2. The compounds or a pharmaceutically acceptable salt thereof, according to claim 1 having the following formula: ##STR43## wherein: A is O or NH; R.sup.1 is C.sub.1-4 or alkyl; R.sup.2 is H or halo; R.sup.3 is H or halo; and Z is (H) (H) or an .alpha.-hydrogen and .beta.-substituent selected from the group consisting of: C.sub.1-4 alkyl, C.sub.1-4 alkoxycarbonylmethyl, and carboxymethyl. 3. The compound, or a pharmaceutically acceptable salt thereof, according to claim 2 having the following formula: ##STR44## wherein: A is O or NH; R.sup.1 is H or C.sub.1-4 alkyl; R.sup.2 is H or fluoro. 4. A pharmaceutical composition having C.sub.17-20 lyase and 5.alpha.-reductase activity comprising a pharmaceutical carrier and an effective inhibitory amount of a compound or a pharmaceutically acceptable salt thereof, of the formula: ##STR45## wherein: A is O or NH; R.sup.1 is H or C.sub.1-4 alkyl; R.sup.2 is H, halo, phenylthio, phenylsulfinyl or phenylsulfonyl; R.sup.3 is H, halo, C.sub.1-4 alkylthio, C.sub.1-4 alkylsulfinyl or C.sub.1-4 alkylsulfonyl; R.sup.4 is H, C.sub.1-4 alkyl or C.sub.2-4 alkenyl; R.sup.5 is H or C.sub.1-4 alkyl; Z is: (a) oxo; (b) (H) (H) or an .alpha.-hydrogen and .beta.-substituent selected from the group consisting of: C.sub.1-4 alkyl, C.sub.2-4 alkenyl, hydroxy, C.sub.1-4 alkanoyloxy, C.sub.1-4 alkoxycarbonylmethyl, carboxymethyl, C.sub.1-4 alkoxycarbonyl, carboxy, C.sub.1-4 alkanoyl and halo; with the proviso that when: (a) R.sup.2 is present and is other than hydrogen, a 1,2 double bond is present, or (b) Z is oxo, a 6,7 double bond is not present, or (c) R.sup.1 is H or C.sub.1-4 alkyl, and R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are H, and Z is (H)(H), and no double bonds exist in any of the positions 1(2), 5(6) or 6(7), A is not NH, or (d) A is O, and Z is (H)(H), and R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are H, R.sup.1 is C.sub.3-4 alkyl. 5. The pharmaceutical composition according to claim 4 having C.sub.17-20 lyase and 5.alpha.-reductase activity comprising a pharmaceutical carrier and an effective inhibitory amount of a compound or a pharmaceutically acceptable salt thereof, of the formula: ##STR46## wherein: A is O or NH; R.sup.1 is H or C.sub.1-4 alkyl; R.sup.2 is H or halol; and R.sup.3 is or halo; and Z is(H) (H) or an .alpha.-hydrogen and .beta.-substituent selected from the group consisting of: C.sub.1-4 alkoxycarbonylmethyl, and carboxymethyl. 6. The pharmaceutical composition according to claim 5 having C.sub.17-20 lyase and 5.alpha.-reductase activity comprising a pharmaceutical carrier and an effective inhibitory amount of a compound or a pharmaceutically acceptable salt thereof, of the formula: ##STR47## wherein: A is O or NH; R.sup.1 is H or C.sub.1-4 alkyl; R.sup.2 is H or fluoro. 7. A method for treating acne which comprises administering to a patient in need thereof an effective inhibitory amount of a compound or a pharmaceutically acceptable salt thereof, of the formula: ##STR48## wherein: A is O or NH; R.sup.1 is H or C.sub.1-4 alkyl; R.sup.2 is H, halo, phenylthio, phenylsulfinyl or phenylsulfonyl; R.sup.3 is H, halo, C.sub.1-4 alkylthio, C.sub.1-4 alkylsulfinyl or C.sub.1-4 alkylsulfonyl; R.sup.4 is H, C.sub.1-4 alkyl or C.sub.2-4 alkenyl; R.sup.5 is H or C.sub.1-4 alkyl; Z is: (a) oxo; or (b) (H) (H) or an .alpha.-hydrogen and .beta.-substituent selected from the group consisting of: C.sub.1-4 alkyl, C.sub.2-4 alkenyl, hydroxy, C.sub.1-4 alkanoyloxy, C.sub.1-4 alkoxycarbonylmethyl, carboxymethyl, C.sub.1-4 alkoxycarbonyl, carboxy, C.sub.1-4 alkanoyl and halo; with the proviso that when: (a) R.sup.2 is present and is other than hydrogen, a 1,2 double bond is present, or (b) Z is oxo, a 6,7 double bond is not present, or (c) R.sup.1 is H or C.sub.1-4 alkyl, and R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are H, and Z is (H)(H), and no double bonds exist in any of the positions 1(2), 5(6) or 6(7), A is not NH, (d) A is O, and Z is (H)(H), and R.sup.2, R.sup.3,R.sup.4 and R.sup.5 are H, R.sup.1 is C.sub.3-4 alkyl. 8. The method according to claim 7 for treating acne which comprises administering to a patient in need thereof an effective inhibitory amount of a compound or a pharmacutically acceptable salt thereof, of the formula: ##STR49## wherein: A is O or NH; R.sup.1 is H or C.sub.1-4 alkyl; R.sup.2 is H or halo; R.sup.3 is H or halo; and Z is (H) (H) or an .alpha.-hydrogen and .beta.-substituent selected from the group consisting of: C.sub.1-4 alkyl, C.sub.1-4 alkoxycarbonylmethyl, and carboxymethyl. 9. A method according to claim 8 for treating acne which comprises administering to a patient in need thereof an effective inhibitory amount of a compound or a pharmaceutically acceptable salt thereof, of the formula: ##STR50## wherein: A is O or NH; R.sup.1 is H or C.sub.1-4 alkyl; R.sup.2 is H or fluoro. 10. The method according to claim 9 wherein the compound administered has the formula: ##STR51## -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION The enzyme steroid C.sub.17,20 lyase cleaves the 17-20 carbon-carbon bond in steroids having a two carbon side chain at the 17.beta.-carbon position to form important precursor molecules to the formation of testosterone, 5.alpha.-dihydrotestosterone and the estrogens, principally estrone and estradiol. Compounds which inhibit this enzyme would thus serve to inhibit the formation of the indicated precursors and thereby be useful in the treatment of various androgenic as well as estrogenic disorders. A treatment incorporating such enzymatic inhibitors is not limited to the origin of the precursor molecule, such as various organ ablation techniques which are currently known. For example, while orchiectomy will effectively reduce gonadal androgen, it will have not have significant effect upon adrenal androgen production. Moreover, such an enzymatic treatment is a much more focused treatment in that it is directed to the immediate hormonal imbalance believed responsible for the condition, as opposed to a broad spectrum remedy which not only affects the particular symptom, but causes permanent endocrine defects necessitating life-long dependency on replacement therapy. It is further known that certain types of breast cancers are estrogen dependent. Adrenalectomy, ovariectomy and hypophysectomy have been employed as well as non-surgical techniques resulting in tumor regressions. It has been shown that human patients with advanced breast cancer, who are administered estrogen biosynthesis enzyme inhibitors, show dramatically reduced plasma estradiol levels and improved therapeutic effects, at least as effective as adrenalectomy. (Jean Van Wauve and Paul A. J. Janssen, Journal of Medicinal Chemistry, 32, 10:2231-2239). Prostatic cancer, or neoplastic tissue disorders which originate in the parenchymal epithelium of the prostate is one of the most common malignancies among men, and exhibits one of the highest cancer-specific deaths of all malignant carcinomas. It is known that patients with metastatic prostate cancer respond positively to hormonal therapy. It is reported by Cookson and Sarosdy that androgen ablation has had a positive, beneficial response for as high as 60% to 80% for all patients tested. (Cookson C. S. and Sarosdy, M. F., South Med. J 87:1-6). More specifically, C.sub.17,20 lyase inhibitors would be useful in the treatment of hormonal dependent prostatic carcinoma, prostatic hyperplasia, virilism, congenital adrenal hyperplasia due to 21-hydroxylase deficiency, hirsutism, hormonal dependent breast cancer, polycystic ovarian syndrome correlated with elevated C.sub.17,21 lyase activity as well as other neoplastic tissue disorders such as endometrial, hepatocellular and adrenal carcinomas. The enzyme steroid 5.alpha.-reductase, present in mammalian tissues including skin, male genitalia and the prostate, catalyzes the conversion of testosterone (17.beta.-hydroxy-androstan-4-en-3-one) into dihydrotestosterone or DHT (17.beta.-hydroxy-5.alpha.-androst-3-one), which is also known as stanolone. DHT is a more potent androgen than testosterone, and acts as an end-organ effecter in certain tissues, particularly in mediating growth. DHT formation can occur in certain tissues themselves by the action of 5.alpha.-reductase. In the treatment of androgen dependent disorders, such as benign prostatic hyperplasia and prostatic cancer, including hormonal dependent carcinoma, the inhibition of DHT would be highly desirable. The conversion of testosterone to DHT itself can be associated with various androgenic disorders, especially when DHT levels build up to excessive amounts. For example, high levels of DHT in the skin has been associated in the pathogenesis of acne, including acne vulgaris. Agents which have the ability to inhibit both C.sub.17-20 lyase and 5.alpha.-reductase would not only inhibit DHT production, but also testosterone formation. In inhibiting the principal androgenic steroidal hormones, such compounds would have enhanced utility in the treatment of androgen disorders. The enzyme C.sub.17 -hydroxylase catalyzes the C.sub.17 hydration of steroid substrates during the biosynthesis of cortisol. As C.sub.17-20 lyase and C.sub.17 -hydroxylase are different active sites of the same enzyme, the inhibition of one usually results in the disabling of the other. Cortisol excess results in a syndrome characterized by hypokalemia, metabolic alkalosis, polydipsia, polyuria, Cushing's syndrome and hypertensive conditions. Inhibition of cortisol synthesis via C.sub.17.alpha.-hydroxylase would therefor have therapeutic effect for the treatment of these disorders or conditions. SUMMARY OF THE INVENTION The present invention relates to 4-aza-17-(cyclopropoxy)-androst-5.alpha.-androstan-3-one, 4-aza-17-(cyclopropylamino)-androst-4-en-3-one and related compounds and to compositions incorporating these compounds, as well as the use of these compounds in the treatment of conditions which would be affected by inhibition of C.sub.17-20 lyase and/or 5.alpha.-reductase, including androgen and estrogen ediated disorders, such as, for example benign prostatic hyperplasia, DHT-mediated disorders, such as, for example, acne, estrogen dependent breast cancer and androgen mediated prostatic cancer. As the present compounds also disable the operation of C.sub.17.alpha. -hydroxylase, disorders which are characterized by an oversynthesis of cortisol can also be treated by the compounds of the invention. For example, hypokalemia, metabolic alkalosis, polydipsia, polyuria, Cushing's syndrome and hypertensive conditions. In another embodiment, the compounds of the invention may be administered in combination with other effective treatment for enhanced therapeutic effect. For example, in the treatment of androgen-dependent disorders, including prostatic cancer, flutamide, a known androgen receptor antagonist may be used in combination with the compounds of the invention. More particularly, the present invention is directed to a group of compounds, and to their pharmaceutically acceptable salts, having the following general formula: ##STR2## wherein: A is O or NH; R.sup.1 is H or C.sub.1-4 alkyl; R.sup.2 is halo, phenylthio, phenylsulfinyl or phenylsulfonyl; R.sup.3 is halo, C.sub.1-4 alkylthio, C.sub.1-4 alkylsulfinyl or C.sub.1-4 alkylsulfonyl; R.sup.4 is H, C.sub.1-4 alkyl or C.sub.2-4 alkenyl; R.sup.5 is H, C.sub.1-4 alkyl; Z can be: a) oxo; b) (H)(H) or an a-hydrogen and a .beta.-substituent selected from the group consisting of: C.sub.1-4 alkyl, C.sub.2-4 alkenyl, hydroxy, C.sub.1-4 alkanoyloxy, C.sub.1-4 alkoxycarbonylmethyl, carboxymethyl, C.sub.1-4 alkoxycarbonyl, carboxy, C.sub.1-4 alkanoyl and halo; with the proviso that when: a) R.sup.2 is present and is other than hydrogen, a 1,2-double bond is present, and b) Z is oxo a 6,7, double bond is not present. DESCRIPTION OF THE FIGURES FIG. 1 Illustrates the tumor volume for individual animals over time of the vehicle control group in PC-82 nude mouse assay. FIG. 2 Illustrates the tumor volume for individual animals over time of the castrated group in the PC-82 nude mouse assay. FIG. 3 Illustrates the tumor volume for individual animals over time of the group administered compound MDL 103432 in the PC-82 nude mouse assay. FIG. 4 Illustrates the tumor volume for individual animals over time of the group administered compound MDL 105,831 in the PC-82 nude mouse assay. FIG. 5 Illustrates the tumor volume for individual animals over time of the group administered compound MDL 15,910 (flutamide) in the PC-82 nude mouse assay. FIG. 6 Illustrates the tumor volume for individual animals over time of the vehicle control group in the Dunning H rat assay. FIG. 7 Illustrates the tumor volume for individual animals over time of the group administered a combined therapy of MDL 105,831 and MDL 15,910 (flutamide) in the Dunning H rat assay. FIG. 8 Illustrates the tumor volume for individual animals over time of the group administered compound MDL 105,831 in the Dunning H rat assay. FIG. 9 Illustrates the tumor volume for individual animals over time of the group administered compound MDL 15,910 (flutamide) in the Dunning H rat assay. FIG. 10 Illustrates the tumor volume for individual animals over time of the castrated group in the Dunning H rat assay. DETAILED DESCRIPTION OF THE INVENTION As used herein, the term "C.sub.1-4 alkyl" means any straight or branched chain alkyl radical of one to four carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and the like. As used herein, the term "C.sub.2-4 alkenyl" means any straight or branched chain alkene radical of two to four carbon atoms. For example, ethenyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butenyl and the like. As used herein, the term "C.sub.1-4 alkylthio, C.sub.1-4 alkylsulfinyl or C.sub.1-4 alkylsulfonyl" means C.sub.1-4 alkyl-Y-, where C.sub.1-4 alkyl is as defined above, and Y is S, SO or SO.sub.2 radical, respectively, and as depicted in Scheme G. "Phenylthio, phenylsulfinyl or phenylsulfonyl" is defined in a similar manner, or Ph--S--, Ph--SO-- or Ph--SO.sub.2 --. As used herein, the term "C.sub.1-4 alkanoyloxy" defines a final product molecule which is the ester condensation product of the corresponding steroid alcohol with a straight or branched chain unsaturated carboxylic acid of from one to four carbon atoms. For example, formyloxy, acetyloxy, n-proprionyloxy, isoproprionyloxy, n-butanoyloxy, s-butanoyloxy, t-butanoyloxy and the like. It is graphically represented by compound 49 in Scheme I or compound 56 of Scheme J. As used herein, the term "C.sub.1-4 alkoxycarbonylmethyl" means a C.sub.1-4 alkyl, as defined above, ester of acetic acid, all of which forms a substituent bonded at the .alpha.-carbonyl carbon to the steroid nucleus, as represented in Scheme K. As used herein, the term "C.sub.1-4 -alkoxycarbonyl" means C.sub.1-4 alkyl, as defined above, ester of formic acid, all of which forms a substituent bonded at the carbonyl carbon to the steroid nucleus, as represented in Scheme L. As used herein, the term "C.sub.1-4 alkanoyl" means a ketone of from one to four carbon atoms, bonded to the steroid nucleus at the carbonyl carbon, as represented in Scheme M. or example, ethanoyl, isopropanoyl, n-butanoyl, s-butanoyl, t-butanoyl. As used herein, the term "halo" means a chloro, bromo or iodo substituent. As used herein, the term "pharmaceutically acceptable salt" is intended to mean any organic or inorganic acid salt which is capable of forming a non-toxic acid addition salt which is suitable for use as a pharmaceutical. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di- and tri-carboxylic acids. For example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, glutamic, gluconic, formic and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid. Further examples of suitable pharmaceutically-acceptable salts are recited in Berge, S. M. et al, J. Pharm Sci. 66:1, 1 (1977), which is herein incorporated by reference. Such salts can exist in either a hydrated or substantially anhydrous form. As used herein, the term "patient" refers to a warm blooded animal such as a mammal which is afflicted with a particular disease. It is explicitly understood that guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep and humans are example of animals within the scope of the meaning of the term. As used herein, the term "effective inhibitory amount", is such an amount wherein an enzyme inhibitory effect is achieved sufficient to cause a therapeutic effect in the patient. The exact amount of compound to be administered can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances. Factors significant in determining the dose include: the dose; the species of animal, its size, age and general health; the specific disease involved, the degree of or involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. That said, the exact amount employed may vary over a wide range. For example, from about 0.625 to 200 mg/kg of body weight per day, preferably from about 0.5 mg to 100 mg/kg of body weight per day. In practicing the methods of this invention, the active ingredient is preferably incorporated into a composition containing a pharmaceutical carrier, although the compounds are effective, and can be administered, in and of themselves. The term "pharmaceutical carrier" refers to known pharmaceutical excipients useful in formulating pharmaceutically active compounds for administration, and which are substantially nontoxic and nonsensitizing under conditions of use. The exact proportion of these excipients are determined by the solubility and chemical properties of the active compound, the chosen route of administration as well as standard pharmaceutical practice. That said, the proportion of active ingredient can vary from about 5% to about 90% by weight. Formulations The pharmaceutical compositions of the invention are prepared in a manner well known in the pharmaceutical art. The carrier or excipient may be a solid, semisolid, or liquid material which can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art. The pharmaceutical composition may be adapted for oral, inhalation, parenteral, or topical use and may be administered to the patient in the form of tablets, capsules, aerosols, inhalants, suppositories, solution, suspensions, powders, syrups, and the like. As used herein, the term "pharmaceutical carrier" means one or more excipients. In preparing formulations of the compounds of the invention, care should be taken to ensure bioavailability of an effective inhibitory amount, including oral, parental and subcutaneous routes. For example, effective routes of administration may include, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally and the like including release from implants as well as direct injection of the active ingredient and/or composition directly into the tissue or tumor sites. Suitable pharmaceutical carriers and formulation techniques are found in standard texts, such as Remington'sPharmacuetical Sciences, Mack Publishing Co., Easton Pa., which is herein incorporated by reference. For oral administration, the compounds can be formulated into solid or liquid preparation, with or without inert diluents or edible carrier(s), such as capsules, pills, tablets, troches, powders, solutions, suspensions or emulsions. The tablets, pills, capsules, troches and the like may also contain on or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel.RTM., corn starch and the like; lubricants such as stearic acid, magnesium stearate or Sterotex.RTM., glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; and flavoring agents such as peppermint, methyl salicylate or fruit flavoring. When the dosage unit form is a capsule, it may also contain a liquid carrier such as polyethylene glycol or a fatty oil. Materials used should be pharmaceutically pure and non-toxic in the amounts used. For parental administration, the compounds may be administered as injectable dosages of a solution or suspension of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water-in-oil or without the additions of a surfactant and other pharmaceutically acceptable excipients. Illustrative of oils which can be employed in the preparations are those of petroleum, animal, vegetable or synthetic origin. For example, peanut oil, soybean oil, and mineral oil. In general, water, saline, aqueous dextrose and related sugar solutions, ethanols and glycols, such as propylene glycol are preferred liquid carriers, particularly for injectable solutions. The parental preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of inert glass or plastic. The solutions or suspension described above may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as ascorbic acid or sodium bisulfite; chelating agent such as ethylene diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The compounds can be administered in the form of a cutaneous patch, a depot injection, or implant preparation which can be formulated in such a manner as to permit a sustained release of the active ingredient. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants. Implants may employ inert materials such as biodegradable polymers and synthetic silicones. Further information on suitable pharmaceutical carriers and formulation techniques are found in standard texts such as Remington's Pharmaceutical Sciences. Chemical Syntheses The following reaction schemes and descriptive text describe the preparation of the various compounds of the invention. Different combinations and permutations to arrive at individual compounds are readily apparent to one of ordinary skill in the art. Scheme A represents a potential syntheses for the C.sub.17 -cyclopropyl-5-ene steroid compounds of the invention starting from testesterone. Testosterone or 17.beta.-hydroxy-androst-5(6)-en-3-one [1] is treated with a strong oxidizer which breaks open the A-ring of the steroid nucleus to give the corresponding 4-nor-3,5-seco-acid [2]. For example potassium permanganate with sodium periodate in aqueous potassium carbonate and tert-butanol or methanolic ozone in methylene chloride at reduced temperature have proved effective. Care should be taken, however, to assure that over-oxidation does not occur, thereby converting the C.sub.17 -hydroxy substituent into a ketone. The seco-acid [2] can be converted into the corresponding lactam or 4-aza steroid [3] by refluxing in the presence of an ammonium acid addition salt and an acid. For example, ammonium acetate in acetic acid. The corresponding 4-alkyl-aza compounds of the invention can be prepared by refluxing with the appropriate alkylamine or alkylamine hydrochloride under acidic conditions. For example, to create the desired 4-methyl-4-aza steroid, the seco-acid [2] is refluxed with methylamine hydrochloride in the presence of acetic acid. The acid addition ester [3] can be converted into the corresponding 17-alcohol [4] under basic hydrolysis conditions, such as aqueous sodium hydroxide in ethanol. Tetrahydrofuran (THF) may be employed, as necessary to assist in the solubility of the steroid substrate. The 17-alcohol [4] can be converted into the vinyl ether [5] by etherification with a vinyl ether in the presence of a suitable etherification catalyst and solvent. For example, ethyl vinyl ether and mercuric acetate in chloroform or chloroform/tert-butyl methyl ether. A. B. Charette, et al., Tet. Lett. 35(4), 513-516 (1994). The vinyl ether [5] can then be converted into the cyclopropyl ether [6] under typical cyclopropanation conditions, such as by reaction with tert-butyl methyl ether, diethyl zinc and methylene iodide in methylene chloride. ##STR3## Scheme B graphically illustrates a synthetic route for the preparation of the saturated B-ring C.sub.17 -cyclopropyl ether compounds of the invention. In Scheme B, Option A, the 5-ene C.sub.17 -acid ester [3] is hydrogenated to the saturated acid ester [7] and then hydrolyzed to the saturated 17-alcohol [8]. Typical hydrogenation conditions include heating with hydrogen in the presence of ethanol and 5% palladium on carbon catalyst. The hydrolysis conditions are similar to those reported under Scheme A, aqueous sodium hydroxide in ethanol and tetrahydrofuran, the solvent choice as necessary to dissolve the reactants. However, the hydrogenation and hydrolysis steps may be reversed, that is, under Option B, the 5(6) unsaturated 17-alcohol [4] is created directly by hydrolyzing the acid ester [3], and then hydrogenated to give the saturated 17-alcohol [8]. The 17-alcohol [8], can then be etherified and cyclopropanated as described in Scheme A to give the 17.beta.-cyclopropylether [9]. By "inert substituent" in the definition of R', it is meant a substituent(s) which is (are) unaffected by the reaction conditions of the scheme. ##STR4## Scheme C illustrate a potential synthesis for the preparation of the compounds of the invention having a 17-cyclopropylamino substituent. The starting compound, testosterone [1] is treated to oxidation conditions sufficient to break open the A-ring of the steroid nucleus to give the corresponding 17-keto-4-nor-3,5-seco-acid [10]. This may be effected in a manner similar to that described for the preparation of compound [2] in Scheme A. Preferably, since oxidation of the C.sub.17 -hydroxy substituent to the C.sub.17 -ketone is desirable, modified reaction conditions from the Scheme A ring cleavage are employed. For example, bubbling ozone at reduced temperature (-78.degree. C.) in methylene chloride and ethyl acetate. Non-alchoholic solvents are employed to ensure that transesterification with the newly formed seco-acid does not occur. The seco-acid [10] is converted into the corresponding 17-keto lactam or 4-aza steroid [11] under the application of conditions similar to those described for the corresponding reaction in Scheme A. For example, refluxing in the presence of ammonium acetate and acetic acid. The 4-alkyl compounds may be prepared in a similar manner, e.g., refluxing in acidic alkylamine or acidic alkylamine hydrochloride. To obtain the 5(6)-olefin, as defined by Route A, the 17-keto lactam [11] is converted into the corresponding 17-cyclopropylimino compound [12] by reaction with cyclopropylamine in chloroform. THF may be used as a cosolvent, if necessary to solubilize the steroid substrate. The cyclopropylimine [12] is reduced to the corresponding 17-cyclopropylamine [13] by reaction with a suitable reducing agent such as sodium borohydride. The saturated cyclopropylamino compounds of the invention can be prepared also under Scheme C following Route B. The 17-keto lactam [11] is hydrogenated preferentially by action of H.sub.2 gas with palladium catalyst to obtain the saturated 17-hydroxy lactam [14]. The 17-alcohol [14] may be oxidized to the corresponding 17-ketone ##STR5## [15] by reaction with tetrapropylammonium perruthenate (VII) (TPAP) and 4-methylmorpholine N-oxide (NMO) in the presence of 4 .ANG. molecular sieves. The 17-ketone [15] is then converted into the corresponding cyclopropylimine [12] and reduced to give the 17-cyclopropylamino compound [13] in a similar manner as described in Route A, above. Scheme D illustrates a potential synthesis for the 1-halo-.DELTA..sup.1 compounds of the invention. The synthesis may begin with the saturated acid ester [7], also an intermediate of Scheme B. To obtain the 1-halo-.DELTA..sup.1 -4-aza compounds of the invention, The acid ester [7] is then dehydrogenated preferentially at the .DELTA..sup.1(2) positions to give the corresponding 1(2)-ene [16], as is known. For example, reaction with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and bis(trimethylsilyl)-trifluoroacetamide (BSTFA) in dioxane. Bhattacharya et al. J.Am. Chem. Soc., 1988, 110, 3318-3319. Under Option A, the hydrolysis, vinylation and cyclopropanation may be performed in a manner similar to that described under Scheme A to give the .DELTA..sup.1(2) -ene-17-cyclopropylether [17]. Under Option B, the 17-cyclopropylamine [17] is formed by first hydrolysing to the 17-alcohol, as under option A, but then oxidizing, cycloaminating and reducing as described under Route B in Scheme C. Compound [17] can be converted into the corresponding 1-phenylthioether [18] by reaction with phenylmercaptan (thiophenol) in sodium hydride. The thioether [18] can be changed into the 1,2-halo compound [19] by reaction with N-bromo-succinimide (NBS) and diethylaminosulfur trifluoride (DAST). Bohlmann, R. Tetrahedron Lett. 1994, 35(1), 85-88. The 2-halo substituent can then be eliminated by reaction with tributyltin hydride and azobisisobutylronitrile to give the desired 1-fluoro-.DELTA..sup.1(2) compound [20]. This compound [20], may be hydrogenated, if desired by reaction with H.sub.2 gas over palladium to give the saturated 1-fluoride [21]. ##STR6## Scheme E graphically represents a potential synthesis for the 1-phenylsulfinyl and 1-phenylsulfonyl compounds of the invention, starting from the 1-phenylthioether [18], the preparation thereof described in Scheme D, as is known. For example, compound 18 may be reacted with 3-chloroperoxybenzoic acid at reduced temperature (-78.degree. C.) for 3 hours under nitrogen to create the 1-phenylsulfinyl thioether. The 1-phenylsulfonyl thioether is created under similar reaction conditions as the sulfinyl ether, except the reaction occurs at room temperature, and the time is extended to 16 hours. ##STR7## Scheme F represents the preparation of the 2.alpha.-halo compounds of the invention, starting from the 4-aza-17-alcohol [14], the preparation thereof is described in Scheme C, Route B. The 17-alcohol [14] is first converted into the protected ether [14] by any effective means, for example by reaction with trimethylsilyl chloride in methylene chloride. The protected ether [14] may then be halogenated by reaction with N,N,N',N'-tetramethylethylenediamine (TMEDA) and the desired halogenated silylating agent at reduced temperature under an inert atmosphere. Once halogenated, the protecting group is removed for subsequent conversion of the 17-substituent. For example, to create the bromide [25], trimethylsilyliodide and bromine in TMEDA and toluene may be used initially, followed by tetrabutyl ammonium fluoride (TBAF) in tetrahydrofuran (THF). Correspondingly, the iodide [26], may be created by trimethylsilylchloride and iodine in TMEDA in toluene, followed by the action of TBAF in THF. The 2.alpha.-halogens [25]-[26] can then be converted into the corresponding 17.beta.-cyclopropylamino compound [27]-[28 as in Scheme C, or the corresponding 17.beta.-cyclopropyloxy compound [27]-[28] as described in Scheme A. ##STR8## Scheme G represents a synthesis for the creation of the 2.alpha.-alky-thio/alkyl-sulfinyl/and alkyl-sulfonyl compounds of the invention starting from the 2.alpha.-iodo -cyclopropyl-ether or -cyclopropylamino compound [28]. The alkyl thioether [29] may be created by reaction with the corresponding alkali metal salt of the alkyl thiol in a suitable solvent, as is known. For example, the methyl thioether may be created by employing sodium thiomethoxide (sodium methyl sulfide; sodium methanethiolate) in ethanol. The sulfoxide [30] and sulfone [31] can then be created as in Scheme E. ##STR9## Scheme H.sub.1 represents a synthesis for the creation of the 7.beta.-alkyl compounds of the invention starting from 17.beta.-hydroxy-androst-5-en-3-ol 3-acetate [32]. In Scheme H.sub.1, compound 32 is first protected by any suitable protecting agent. For example, t-butyldimethylsilyl chloride and diazabicyclo[5.4.0]undec-7-ene (DBU) in methylene chloride. The protected acetate [33] is then C.sub.7 -oxidized to create the 7-ketone [34] by any known means. For example, by reaction with t-butylchromate in acetic anhydride, acetic acid and carbon tetrachloride. Pinto, A. et al., Chem. Pharm. Bull. 1988, 36(12), 4689-4692. The 7-ketone is then reacted with the appropriate Grignard to give the corresponding 7-alkyl-7-alcohol [35]. For example, the 7-ethyl-7-alcohol may be formed by reaction with ethylmagnesium chloride in THF. For example, the 7-aryl-7-alcohol can be formed by reaction with 4-bromotolylmagnesium chloride in THF. The 7-substituted-7-alcohol [35] is dehydrated to the 7-alkyl diene [36] by reaction in a suitable matter, such as for example, by reaction with aluminum isopropoxide in the presence of toluene and cyclohexanone. Eastham, J. F. & Teranihi, R., Org. Synth., Coll. Vol. IV 1963, 192-195; Djerassi, C. Org. React. 1961, 6, 207-272. The diene [36] can then be hydrogenated and isomerized under known conditions to give the olefin [37]. For example, reaction with dry ammonia and lithium metal in t-butanol and toluene. Crabtree et al. Org. Synth. 1991, 70, 256-264; Caine, D. et al. Org. Synth. Coll. Vol. VI 1988, 51-55; Caine D. Org. React. 1976, 23, 1-258. ##STR10## In Scheme H.sub.2, the olefin [37] can be isomerized and desilyated to the 4-en-17-alcohol [38] by any appropriate reagents. For example, reaction with 1,8-diazabicyclo [5.4.0]undec-7-ene at reflux followed by cooling to room temperature and reaction with tetrabutylammonium fluoride. Under Route A, compound [38] is then oxidized, lactamized and hydrolyzed as described in Scheme A to give the 4-aza-17-alcohol [39], which can then be etherified and cyclopropanated as in Scheme A to give the corresponding cyclopropyl ether [40]. In the creation of the cyclopropylamine [42] under Route B, the 17-alcohol [39] can be oxidized to the ketone [41] and then cycloaminated and reduced as in Scheme C, Route B. However, it is also readily apparent that the cyclopropylamine can be prepared from the 17-alcohol [38] with fewer synthetic steps by performing the oxidative ring cleavage, lactamization, cycloamination and reduction as described in Scheme C, Route A (not shown in Scheme H.sub.2). ##STR11## Scheme I graphically describes a synthesis for the 7-hydroxy-, 7-oxo- and 7-alkanoyloxy-17.beta.-cyclopropyl ether compounds of the invention from 3.beta.-acetoxy-17.beta.-t-butyldimethylsilyloxy-androst-5-en-7-one [34]. Compound [34] is ketalized under appropriate known reaction conditions, such as, for example reaction with 1,2-bis(trimethylsiloxy)ethane and trimethylsilyl trifluoromethanesulfonate in methylene chloride at -78.degree. C., to give the 7-ketal 3-acetate [43]. Tsunoda, T. et al., Tetrahedron Lett. 1980, 21 (14), 1357-1358; Hwu, J. R. et al., J. Org. Chem. 1987, 52(2), 188-191. Compound [43] is hydrolyzed as in Scheme A followed by oxidation to the 3-ketone [44]. The oxidation may be carried out, for example, similarly as the conversion of of compound [35] to [36] in Scheme H.sub.1, i.e., refluxing with aluminum isopropoxide in the presence of toluene and cyclohexanone. The 3-ketone [44] is then desilylated/isomerized, oxidized, lactamized and hydrolyzed as described in Scheme H.sub.2 to give the 17-alcohol [45]. The 17-alchohol [45] can then be etherified and cyclopropanated as in Scheme A to give the 3,7-dioxo-17.beta.-cyclopropyl ether [46]. The cyclopropyl ether [46] can be reduced directly into the 7-alcohol [48], as is indicated in Option A, or it can first be hydrogenated to compound [47] and subsequently reduced, as indicated in Option B. The reduction conditions may be similar to those used in previous Schemes, for example, sodium borohydride in ethanol and THF. The hydrogenation may also be carried out in a manner similar to that described previously (Scheme B), for example, heating in the presence of hydrogen and palladium catalyst. The cyclopropylether 7-alcohol [48] may be esterified into alkyl alcohol esters [49] by reaction with the appropriate alkyl anhydrides. For example, to create the alcohol ester of proprionic acid, compound [48] is reacted with prionic anhydride in pyridine. Baer, H. H. et al., Can. J. Chem. 1991, 69, 1563-1574. ##STR12## In Scheme J, there is illustrated the preparation of the 7-oxo-, 7-hydroxy- and 7-alkoxycarbonyl-17-cyclopropyl-amino compounds of the invention, starting from the 17.beta.-hydroxy-3,7-dione [45], also an intermediate of Scheme I. Compound [45] is first deprotonated and then immediately silylated to create the protected ether [50]. Suitable conditions include, for example, reaction with lithium diisopropylamide followed by trimethylsilyl chloride at -78.degree. C. The protected ether [50] can then be dehydrogenated and 7-silyated and acid hydrolyzed in the conventional manner. Suitable reaction conditions include, for example, treatment with lithium diisopropylamide in THF at -78.degree. C. followed by addition of t-butyldimethylsilyl chloride. Once this reaction product is worked-up, it can be acid hydrolyzed with acetic acid in THF to give the 17-alcohol-7-protected ether [51]. Compound [51] can then be oxidized, cycloaminated and reduced as in Scheme C, Route B to give the protected cyclopropylamine [52]. Compound [52], when deprotected, affords the 3,7-dioxo cyclopropylamine [53]. Suitable conditions for this conversion, include for example, tetrabutylammonium fluoride in THF under an inert atmosphere. The remaining compounds in the Scheme [54], [55] and [56] may be made in a manner similar to that described under Scheme I. ##STR13## Scheme K graphically illustrates a potential preparation of the 7-alkoxycarbonylmethyl and 7-carboxymethyl compounds of the invention starting from compound [50], also an intermediate in Scheme J. The protected 7-ketone [50] is carboxylated to form the alkylcarbonyloxymethyl diene [57] depicted. For example, the 7-ethyl methylcarboxylate may be created by reaction with triethyl phosphonoacetate in THF and sodium hydride. The diene [57] can then be desilylated and hydrogenated to the 17-alcohol [58] in the typical manner, such as by treatment with tetrabutylammonium fluoride in THF. The 17-alcohol [58] can be converted to the cyclopropylether [59], depicted under Option A, similarly as described in Scheme A. Alternatively, the 17-alcohol [58] may be converted into the cyclopropylamine [59], depicted under Option B, similarly as described in Scheme B. Compound [59] then may be base hydrolyzed in the conventional manner (Scheme A) to give the 7-ethanoic acid [60]. ##STR14## Scheme L graphically illustrates a synthesis of the 7-alkoxycarbonyl and 7-carboxylic acid compounds of the present invention starting from the 7-alkyl ethanoate [58], also an intermediate in Scheme K. The carbonyl is phenylated in the conventional manner, for example, by reaction with phenylmagnesium chloride (4 molar eq.) in THF to give the 7-diphenyl-methyl alcohol [61]. This compound [61] can then be dealkylated to the 7-acid [62], as is known. For example, reaction with chromium trioxide (chromic acid) in water, methylene chloride and acetic acid. Riegal, B. et al. Org. Synth. Coll. Vol. 3 1955, 234-236; Subramanium, C. S., et al. Synthesis 1978, 468-469. The 7-acid [62] may then be converted into the alkyl ester [63], as is known. For example, 4-(dimethylamino)-pyridine and 1,3-dicyclohexylcarbodiimide in methylene chloride and ethanol. Neises, B. and Steglich, W. Org. Synth. 1984, 63, 183-187. The ester [63] can then be converted into either the cyclopropylether [64A] (Scheme A) or the cyclopropylamine [64B] (Scheme C) as has been described previously. Compound [64] may subsequently be base hydrolyzed in the conventional manner (e.g. NaOH in water, ethanol and/or THF) to the 7-acid [65]. ##STR15## Scheme M illustrates the preparation of the 7.alpha.-ketone compounds of the invention starting from the 7-alkyl ester [63]. The ketone [63], is first reduced to the corresponding alcohol in the conventional manner (e.g., sodium hydride in ethanol), and silylated as in Scheme H.sub.1 to give the protected ester [66]. The ester ([66] is then reduced to the 7-methyl alcohol [67]. Suitable reduction conditions include, for example, lithium borohydride in THF. Jeanloz, R. W. & Walker, E. Carbohydrate Res. 1967, 4, 504 and Walker, E. R. H. Chem. Soc. Rev. 1976, 5, 23-50. The alcohol is then oxidized into the 7-aldehyde [68]. Suitable oxidation conditions include, for example, 4-hydroxy-TEMPO benzoate in methylene chloride and sodium bicarbonate followed by sodium bromite. Inokuchi, T. et al., J. Org. Chem. 1990, 55, 462-466. The 7-aldehyde [68] is then alkylated to give the .alpha.-ketone alcohol, [69] which is then oxidized and desilylated in the conventional manner (Schemes C and J, respectively) to give the 17-hydroxy-7-alkanone [70]. For example, to create the 1-propanone, titanium tetrachloride and tetraethyl lead are sequentially added at -78.degree. C. in methylene chloride. Yamamoto, T. and Tamada, J. I. J. Am. Chem. Soc. 1987, 109, 4395-4396. Compound [70] can then be prepared as the cyclopropyl ether (Option A, Scheme A) or as the cyclopropylamine [70]. In the preparation of the cyclopropylamine, the 7-alkanoyl group must first be protected by suitable means, such as by formation of the ethylene or 2,2-dimethyl propane ketal, followed by the steps described in Option B, Scheme C, and subsequent deprotection. The protection may be effected, for example by ethylene glycol or 2,2-dimethyl-propan-1,3-diol, respectively, with acid catalysis and deprotected under acid conditions taking care to minimize reaction with the acid-sensitive C.sub.17 -cyclopropylamine, as is known. ##STR16## Scheme N graphically illustrates a potential synthesis for the C.sub.16 -alkenyl and C.sub.16 -alkyl compounds of the invention, starting from androstenedione (androst-4-ene-3,17-dione) [72]. Compound [72] is treated in a manner similar to the procedure described in Scheme C to create the aza-androstenedione [11]. The dione can then be C.sub.16 -alkylated by known techniques to give the 16-alkenyl dione [73]. For example, to create the 16.alpha.-allyl dione, diethyl oxalate and sodium methoxide are sequentially added in methylene chloride solvent at 0.degree. C., followed by reaction with methyl iodide at 55.degree. C., and finally treatment with sodium methoxide. Carruthers, N. I. et al. J. Org. Chem. 1992, 57(3), 961-965. The alkenyl dione [73] can then be transformed into the cyclopropylether (Scheme A) or the cyclopropylamine (Scheme C) as previously described to give the 16-alkene [74]. The 16-alkene [74] may then be hydrogenated in the conventional manner, [Scheme B] to give the 16-alkane [75]. ##STR17## Scheme O.sub.1 graphically represents the first part of a synthesis for the preparation of the 15-alkyl compounds of the invention starting from dehydroisoandrosterone 3-acetate (3.beta.-acetoxy-5-androsten-17-one). The 3-acetoxy-17-one [76] can be ketalized at the C.sub.17 position in the conventional manner (Scheme I) to give the 17-ketal [77]. The ketal [77] is .alpha.-brominated to give the 16-bromide [78]. Suitable bromination conditions include, for example, pyridinium perbromide in dry THF, followed by treatment with sodium iodide, then reaction with sodium thiosulfate in water and pyridine. The bromide [78] can then be dehydrogenated and 17-hydrolyzed into the 15-en-17-one. Typical dehydrogenation conditions include, for example, potassium t-butoxide in dimethylsulfoxide. Typical hydrolysis conditions include, for example, p-toluenesulfonic acid monohydrate. The ketone, prepared by hydrolyzing the ketal, can then be silylated in the conventional manner (Scheme H.sub.1) to give the silylated diene [79]. The silylated diene [79] can then be selectively alkylated at C.sub.15 to give the 15-alkyl silylated 17-ketone [80], as is known in the art. For example, to create the 15-ethyl compound, compound [79] may be dropwise added to ethylmagnesium chloride in ether previously treated with cuprous chloride in THF. The silyated ketone [80] may then be deprotected and oxidized in the conventional manner (Scheme I, Scheme H.sub.1 [35] to [36], respectively) to give the alkylated dione [81]. The alkylated dione [81] is then converted into the seco acid (ring cleaving) and ring closure in the typical manner, as described in Scheme C to give the aza-dione [82]. ##STR18## Scheme O.sub.2 represents the second part of the synthesis of the 15-alkyl compounds of the invention. The aza-dione [82] can be directly converted (Route B) into the desired cyclopropyl ether [84A] (Option A) or cyclopropylamine (Option B) [84B] in the conventional manner (Scheme A and Scheme C, respectively). Alternatively, the aza-dione can be hydrogenated (Route A), under typical conditions (Scheme N) to give the 15-alkyl-aza-androstane [83], which can be converted into either the cyclopropylether [84] or cyclopropylamine [84] as described before. ##STR19## 7-alkyl Compounds The 7-alkyl compounds of the invention may be prepared in a manner analogous to that described in PCT applications PCT/US/04643 (WO 93/23420) and PCT/US/04734 (WO 93/23039) the disclosures of which are hereby incorporated by reference. 7-alkenyl, Carboxy and Methyl Carboxy The compounds of the invention wherein there is an alkenyl, carboxy or methylcarboxy substitent at the 7-position may be prepared in a manner analogous to that presented in PCT applications PCT/US/04643 (WO 93/23420) and PCT/US/04734 (WO 93/23039) the disclosures of which are hereby incorporated by reference. 2-halogenated The compounds of the invention wherein there is a halogen substituent at the 2-position may be prepared by the method described in European Patent Application 0473225 A2 (91-202135), the disclosure of which is herein incorporated by reference. 2-halo, R-thio, R-sulfinyl-, R-sulfonyl The compounds of the invention wherein the above 2-substituents are present may be prepared in a manner analogous to that described in European patent application 0473226 A2 (91-202135), the disclosure of which are herein incorporated by reference. .DELTA..sup.1 dehydrogenation .DELTA..sup.1 dehydrogenation by DDQ in the presence of a silyated agent bistrimethylsilyltrihaloacetamide, hexamethyldisilane or bistrimethylsilylurea are described in U.S. Pat. No. 5,116,983, the disclosure of which is herein incorporated by reference. 15-alkyl The compounds of the invention wherein the there is a 15-alkyl substitution may be prepared in a manner analogous to that reported in PCT Application No. PCT/US94/02697 (WO 94/20114), the disclosure of which is herein incorporated by reference. BIOLOGICAL METHODS & RESULTS The following abbreviations are hereafter employed: NADPH=hydrogenated nicotinamide adenine dinucleotide phosphate DMSO=dimethylsulfoxide EDTA=ethylenediaminetetraacetic acid In vitro C.sub.17,20 lyase assays: Compounds were tested for inhibition of cynomolgus monkey C.sub.17,20 lyase in vitro using microsomal preparations of the enzyme from testicular tissue. Testes were removed from anesthetized animals and flash frozen in liquid nitrogen. Microsomes were isolated as described in Schatzman et al., Anal. Biochem. 175, 219-226 (1988). The compound to be tested was dissolved in dimethyl sulfoxide and diluted in 0.05 M potassium phosphate buffer, pH 7.4, to give the desired concentrations of test compound, in an amount which contributed 0.1% v/v DMSO to the total assay volume. Assays contained 0.05 M potassium phosphate buffer, pH 7.4, an NADPH regenerating system (1 mM NADPH, 5 mM glucose-6-phosphate, 1 IU/mL glucose-6-phosphate dehydrogenase), test compound, substrate and microsomal protein in a total volume of 0.2 mL. Control assays contained all components, including dimethyl sulfoxide, but not test compound. All assays were performed in duplicate. The test compound was incubated with 20 to 62 .mu.g/mL microsomal protein, buffer, and the NADPH regenerating system described above at 34.degree. C. for 0 or 40 minutes. Aliquots of 180 .mu.L were then removed and assayed for enzyme activity by addition to 7-[.sup.3 H]-17.alpha.-hydroxypregnenolone (11.2 mCi/mmole; 0.2 .mu.Ci per assay) plus unlabeled 17.alpha.-hydroxypregnenolone dissolved in DMSO, contributing 2.5% v/v to the final assay mix, and phosphate buffer to give a total substrate concentration of 0.05 .mu.M (=Km) per assay and subsequent incubation at 34.degree. C. for 6 minutes. Each assay was terminated by addition of 5 mL of chloroform:methanol (2:1). Carrier steroids representing substrates and products (17.alpha.-hydroxypregnenolone, dehydroepiandrosterone, and androst-5-ene-3.beta., 17.beta.-diol) and 0.8 mL of distilled, deionized water were also added at this time. The steroids were extracted by the method of Moore and Wilson (Methods in Enzymol., eds. O. Malley, B. W. and Hardman, J. G. 36, 1975, pp. 466-474). The organic phase containing the steroids was evaporated using nitrogen gas, the residues dissolved in 18% tetrahydrofuran (v/V) in hexane, and the steroids were separated by HPLC on a Si60 (5 .mu.m) column (250.times.4 mm) using a gradient of 18-22% tetrahydrofuran (v/v) in hexane. Radioactivity in the steroid peaks was measured using a Radiomatic.RTM. Model HS or Model A515 Flo-One.RTM. detector. The enzyme activity for each assay was calculated from the percent conversion of substrate to products, and the results were expressed as percent inhibition of control. The following results were obtained, wherein the values indicated are the mean of duplicate determinations: TABLE 1 In Vitro C.sub.17,20 Lyase Inhibition Conc. Preincubation Compound (.mu.M) time (min.) % Inhibition MDL 103,129 10 0 77.3 40 84.3 1 0 40.7 40 46.9 0.1 0 6.4 40 18.3 MDL 103,432 10 0 68.3 40 80.2 1 0 33.0 40 54.2 0.1 0 23.4 40 20.2 MDL 103,496 10 0 39.2 40 87.7 1 0 29.0 40 62.2 0.1 0 5.0 40 26.6 MDL 104,313 10 0 63.6 40 70.2 1 0 23.8 40 39.9 0.1 0 -18.4 40 -8.7 MDL 105,831 10 0 69.6 40 100 1 0 26.0 40 53.8 0.1 0 11.4 40 24.6 LEGEND: MDL 103,129 = 17.beta.-Cyclopropyloxy-4-aza-5.alpha.-androst-1-en-3-one MDL 103,432 = 17.beta.-Cyclopropyloxy-4-aza-5.alpha.-androstan-3-one MDL 103,496 = 17.beta.-Cyclopropyloxy-4-aza-androst-5-en-3-one MDL 104,313 = 17.beta.-Cyclopropyloxy-4-methyl-4-aza-androst-5-en-3-one MDL 105,831 = 17.beta.-Cyclopropylamino-4-aza-androst-5-en-3-one In vitro 5.alpha.-reductase assays: The activity of the present compounds as inhibitors of steroid 5.alpha.-reductase was determined using microsomal preparations of the 5.alpha.-reductase enzyme from laboratory animal prostate tissue. Specifically, microsomes were isolated from cynomolgus monkey prostate tissue. Protein concentration of the microsomal preparations was determined prior to use of the samples. Individual assays of cynomolgus monkey prostatic 5.alpha.-reductase activity contained 0.1 M potassium phosphate-sodium citrate buffer, pH 5.6 1.0% (w/v) bovine serum albumin, 1.0 mL sodium EDTA, 4 .mu.g of microsomal protein, 1.0 mM NADPH, 5.0 mM glucose-6-phosphate, 1 IU/mL glucose-6-phosphate dehydrogenase, [1,2-.sup.3 H]-testosterone (0.15 .mu.Ci) plus unlabeled testosterone to yield 0.015 .mu.M (Km=0.015 .mu.M to 0.09 .mu.M in multiple determinations), and test compound which was dissolved in DMSO then diluted in 0.1 M potassium phosphate-sodium citrate buffer, pH 5.6, to yield a final assay concentration of 0.1% (v/v) DMSO. The same buffer and DMSO without test compound were used in control assays. Background radioactivity was determined from assays containing all components except enzyme. Assays were performed in duplicate. Microsomes, 0.1 M potassium phosphate-sodium citrate buffer, pH 5.6, and test compound were preincubated at 37.degree. C. Aliquots of 180 .mu.L were removed after 0 or 40 minutes of preincubation and added to 20 mL of testosterone substrate suspended in 0.1 M potassium phosphate-sodium citrate buffer, pH 5.6, containing 10% (v/v) DMSO. Remaining enzyme activity was assayed for 10 minutes at 37.degree. C. in a Dubnoff shaker incubator. The reactions were terminated by the addition of 5 mL CHCl.sub.3 :methanol (2:1) and 0.9 mL water. Carrier steroids were added in the form of 2.5 .mu.g each of testosterone, dihydrotestosterone, and 3,17-androstanediol. Steroid metabolites were then extracted according to the procedure of Moore and Wilson (Methods in Enzymol., O'Malley, B. W. and Hardman, J. G. eds., 36, 1975, pp. 466-474), the organic phase containing the steroids was evaporated using nitrogen gas, the residues were dissolved in 3% (v/v) isopropanol in hexane. The steroids were then seperated by normal phase HPLC on a LiCrosorb.RTM. DIOL derivatized silica gel column (10 .mu.m; 4.times.250 mm) with a 3% to 7% isopropanol in hexane gradient, followed by isocratic conditions of 75% (v/v) isopropanol in hexane. Radioactivity in the steroid peaks was measure using a Packard Radiomatic model HS Flo-One.RTM. detector. When the compound were tested using the above procedures with cynomolgus monkey 5.alpha.-reductase, the following results were obtained: TABLE 2 In Vitro 5.alpha.-Reductase Inhibition Results Conc. Preinc., time Compound (.mu.M) (min.) % Inhibition MDL 103,432 10 0 99.4 40 99.4 1 0 98.7 40 99.3 0.1 0 78.7 40 80.0 MDL 103,496 10 0 99.6 40 99.4 1 0 86.2 40 86.7 0.1 0 24.6 40 29.5 *NOTE: Values are the mean of duplicate determinations See Table 1 for chemical names Ex vivo inhibition of C.sub.17,20 lyase: MDL 103,432 was tested for ex vivo inhibition of rat and nude mouse testes layse. Male Copenhagen rats and male athymic nude mice obtained from Harlan Laboratories, Indianapolis, Ind., were divided into groups of 5 to 6 based on weight. Average weight was 100-140 g each for rats and 18-35 g each for the mice. Prior to oral dosing, animals were fasted overnight. Test compound was prepared by micronization in a lecithin vehicle using a glass Teflon.RTM. pestle-type homogenizer. The compound was brought to volume using lecithin so as to administer 0.5 mL per 100 g animal. Rats and nude mice were given vehicle only (controls) or vehicle plus test compounds per os. Rats were also given the compound in lecithin or lecithin alone subcutaneously. Each group consisted of 5-6 animals. At a specified time after dosing, the animals were anesthetized with CO.sub.2 gas, sacrificed by cervical dislocation, testes were excised, capsules were removed, and the tissue was weighed. Two volumes (w/v) of 0.05 M potassium phosphate buffer, pH 7.2, was added to the rat testes tissue on ice, and 11 volumes (w/v) of the same buffer were added to the mouse testes. Tissue was then homogenized using 20 strokes with a Dounce homogenizer equipped with a tight pestle. Homogenized tissue was centrifuged at 800.times.G then at 10,000.times.G for 15 minutes each. Supernatant was decanted, reserved, and kept chilled on ice. Assays for lyase activity contained the same buffer and NADPH regenerating system described above and also contained 120 .mu.L of 10,000.times.G supernatant which was diluted 3-fold resulting in a 5-fold dilution overall in the final assay volume. Substrate, 17.alpha.-hydroxyprogesterone plus 1,3-[.sup.3 H]-17.alpha.-hydroxyprogesterone (40-57 mCi/mmole; 0.18 .mu.Ci per assay) to yield a final concentration of 0.1 .mu.M, (=Km) was added to the remaining assay components after a 5 minute equilibration a 20.degree. C. of the latter. The total assay volume was 200 .mu.L. Activity was assayed for 20 seconds at 20.degree. C. Nude mouse testes lyase was assayed by the same procedure described for the rat enzyme above except that the 10,000.times.g supernatant was diluted 12-fold in phosphate buffer, and 60 .mu.L of this was used in the assay resulting in a 40-fold overall dilution of the supernatant. The substrate concentration was 0.04 .mu.M (Km=0.03 .mu.M), and the assays were incubated at 15.degree. C. for 30 seconds. Assays were terminated, extracted and analyzed as described above except that carrier steroids were 17.alpha.-hydroxyprogesterone, androst-4-ene-dione, and testosterone. The organic phase containing the steroids was evaporated using nitrogen gas, the residues dissolved in 18% tetrahydrofuran (v/V) in hexane, and the steroid substrate, 17.alpha.-hydroxyprogesterone, and products (AED, TEST) were separated by HPLC on a Si60 (5 .mu.m) column (250.times.4 mm) using 20% (v/v) tetrahydrofuran (THF) in hexane for 20 minutes then ramping to 60% THF (v/v) for 11 minutes. Activity of test compound was expressed as percent inhibition relative to the control and was the mean of each group of treated animals. Using the method described above, MDL 103,432 inhibited nude mouse testicular C.sub.17,20 lyase activity by 88% at 30 mg/kg and 96% at 100 mg/kg 4 hours after oral dosing. Rat testicular C.sub.17,20 lyase activity was inhibited by MDL 103,432 as shown below: TABLE 3 Ex Vivo C.sub.17,20 Lyase Inhibition Results Dose Time (hr) Route % Inhibition 50 mg/kg 4 p.o. 66.4 50 mg/kg 24 p.o. 52.7 50 mg/kg 4 s.c. 32.9 50 mg/kg 24 s.c. 40.7 In vivo data: Dunning H Tumor As described in J. T. Isaacs & D. S. Coffey, Cancer Res. 41:6070-5075 (1981); W. J. Ellis & J. T. Issacs, Cancer Res. 45:6041-6050 (1985); T. W. Redding & A. V. Schally, The Prostate 6;219-232 (1985) and P. E. Juniewicz et al. The Prostate 18:105-115 (1991), male Copenhagen rats were obtained from HARLAN-SPRAGUE-DAWLEY Inc. (Indianapolis, Ind.), and were individually housed in suspended wire cages and provided laboratory rodent chow (Purina 5001] pellets, Purina Mills, St. Louis, Mo.) and deionized water adlibum. The rats were anesthetized using sodium pentobarbital and the hair was clipped from the back dorsal area. Tumors from donor Copenhagen rats were cut into fragments of 10 mm.sup.3 and implanted subcutaneously (one site per rat) into the prepared dorsal area. Animals were selected (105 days post implantation) for the treatment phase based on tumor size. Ten animals were anesthetized with sodium pentobarbital and bilaterally castrated. The remaining animals were assigned to treatment groups (ten per group) based on mean group tumor size. Animals were kept separate throughout the study. The tested compounds were prepared in solution or suspension in a lecithin vehicle (L-.alpha.-phosphatidycholine type XV-E) containing methylparaben and propylparaben. All treatments were performed by oral gavage (per os) at 2 cc/kg each day of study. Tumor size and rat body weights were recorded every seven days over a period of 35 days. Twenty-four hours after the last treatment animals were euthenized by CO.sub.2 and the tumors, prostate, seminal vesicles and testes were removed and weighed. In Table 4, average tumor growth is determined from the corrected group means over a 35 day period after treatment was started. The correction was determined by first eliminating those animals from each data set which exhibited grossly disproportionate growth relative to the other animals in the treatment group. As these tumors were in-fact rat sarcomas, and the phenomenon was observed in all of the compound treated animals, such disproportionate growth is believed to be a limitation indemic to this model. The animals eliminated from the calculation of the corrected means were in FIG. 6, animals 8, 9, 10; in FIG. 7, animals 18, 19 and 20; in FIG. 8, animals 27, 28, 29 and 30; and in FIG. 9, animals 37, 39 and 40. The castrated controls in FIG. 10 present a different problem. Here it is believed that the different tumor volumes observed throughout the group is attributable to the different sizes at the beginning of the study. Since the mean variance here is clearly attributable to factors other than the effect of the castration itself, animals 47, 48, 49 and 50 were deleted from the corrected mean. Of these, animal 47 died during the treatment period. Table 4 indicates the average daily growth rate, measured from the corrected mean tumor size on day 35 and day 0, comparing MDL 10583 and flutamide (MDL 15910), a known androgen receptor antagonist. MDL 10583 is shown to have similar tumor suppression properties as flutamide which is additive when combination therapy is employed. TABLE 4 Tumor Growth in Dunning H Rat (mm.sup.3) Treatment Day .DELTA.v/.DELTA.t Group 0 7 16 21 29 35 (day 35 .+-. day 0) Vehicle 327.83 594.75 898.67 1143.17 1556.33 1735.67 40.22 mm.sup.3 /day control Castrated 330.17 429.58 508.50 501.00 450.83 220.33 -3.14 mm.sup.3 /day control MDL 105831 & 326.57 439.38 489.00 606.43 773.00 750.43 12.11 mm.sup.3 /day MDL 15910 MDL 105831 328.40 389.90 497.20 759.40 1135.80 1041.60 20.38 mm.sup.3 /day MDL 15910 317.00 604.64 877.86 851.29 1313.57 1214.57 25.64 mm.sup.3 /day LEGEND: MDL 105831 = 17.beta.-cyclopropylamino-4-aza-androst-5-en-3-one (15 mg/kg/day PO) MDL 15910 = N-(3-Trifluoromethyl-4-nitro-phenyl)-isobutyramide (50 mg/kg/day PO) PC-82 Tumors in Nude Mice: As described in van Steenbrugge, G. J. et al., J. Urol 131: 812-817 (1984) van Steenbrugge G. J. et al., The Prostate 11: 195-210 (1987) and Redding, T. W. et al., Cancer Research 52, 2538-2544 (1992), male nude mice (Hsd:athymic, Nude-nu) were obtained from Harlan Sprague Dawley. Mice were housed in sterilized micro-isolators and fed autoclaved ABLE.RTM. rodent chow (Purina Mills Inc., St. Louis, Mo.) and deionized water, ad libitum. Tumor-donating mice were first anesthetized using sodium pentobarbital and then sacrificed by cervical dislocation. The tumor was subsequently excised and placed in a petri dish containing ice-cold Hanks balanced salt solution. Tumors were cut into 2-3 mm cubes for implantation. Recipient animals were first anesthetized with 50 mg/kg pentobarbital, then implanted, by use of a trocar, with tumor fragments (one per mouse) in the dorsal area. Animals were separated into two control groups, one with vehicle alone and the other castrated, and the treatment groups, where n is the number of animals in each group. Animals were selected for treatment groups based on tumor size. Each test compound was prepared as a solution or suspension in a lecithin vehicle (L-.alpha.-phospha-tidycholine type XV-E) containing methylparaben and propylparaben at a dose volume of 10 cc/kg. Animals were treated for 42 days by oral gavage (per os) seven days per week. Twenty-four hours after the last treatment the animals were euthenized by CO.sub.2 and tumors were removed and weighed. During the study period, mice were weighed and palpated weekly for tumors. In Table 5, average tumor growth is determined from the corrected group means over a 28 day period after treatment was started. The correction was determined by first eliminating those animals from each data set which exhibited grossly disproportionate growth relative to the other animals in the treatment group. Such tumor growth is believed to result from conversion of the tumor into a non-androgen dependent sarcoma and most often resulted in euthanasia of the subject before the end of the treatment period. The following animal data was deleted before computation of the corrected mean data in Table 5, FIG. 1: animals 4 and 44; FIG. 2: animals 10, 38 and 42; FIG. 3: Animal 39; FIG. 4: Animals 8, 9 and 49; FIG. 5: Animals 37 and 40 and 41. Table 5 illustrates the average tumor growth in animals treated with 4-aza-17.beta.-(cyclopropyloxy)-5.alpha.-androstan-3-one (MDL 103432; 50 mg/kg B.I.D.), 4-aza-17.beta.-(cyclopropylamino)-5.alpha.-androst-5-ene-3-one (MDL 105831; 50 mg/kg B.I.D.) and flutamide (MDL 15,910; 15 mg/kg B.I.D.), a known androgen receptor antagonist. The average rate of each tested compound relative to the vehicle and castrated controls is consistent with the invivo inhibition of androgens. TABLE 5 Tumor Growth in PC-82 Human Tumor in Male Nude Mice (mm.sup.3) Treatment Day .DELTA.v/.DELTA.t Group -4 7 15 21 28 35 (day 35 - day 7) Vehicle 142.0 245.2 281.9 413.4 505.9 604.1 12.82 mm.sup.3 /day control Castrated 135.9 164.7 165.9 174.9 165.5 199.9 1.26 mm.sup.3 /day control MDL 103432 122.2 180.2 220.2 288.2 385.9 427.4 8.83 mm.sup.3 /day MDL 105831 124.9 188.3 254.3 304.3 530.7 531.1 12.24 mm.sup.3 /day MDL 15910 138.7 222.7 262.9 319.7 563.4 479.3 9.16 mm.sup.3 /day EXAMPLES The following examples are given to better illustrate the syntheses of particular compounds of the invention and should not be construed as limiting the invention in any way. DEFINITIONS In the following examples, unless otherwise noted: "room temperature" means 18.degree. C.-23.degree. C., any reference to "overnight" means 14-18 hours and soluted reagents are in aqueous solutions. The following formula abbreviations have also been employed: brine = saturated aqueous of sodium chloride (NaCl) THF = tetrahydrofuran NaHCO.sub.3 = sodium bicarbonate EtOAc = ethyl acetate CH.sub.2 Cl.sub.2 = methylene chloride MgSO.sub.4 = magnesium sulfate ether = diethyl ether (CH.sub.3 CH.sub.2).sub.2 O HOAc = acetic acid NH.sub.4 Cl = ammonium chloride Na.sub.2 SO.sub.3 = sodium sulfite |
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