Abstract:
Prodrugs of C-17-heterocyclic-steroidal drugs providing improved oral bioavailability and phamacokinetics are described. The drugs are inhibitors of human CYP 17 enzyme, as well as potent antagonists of both wild type and mutant androgen receptors (AR), and are useful for the treatment of urogenital and/or androgen-related cancers, diseases and/or conditions, such as human prostate cancer, breast cancer, and prostate hyperplasia. The disclosure describes methods of synthesizing and using the prodrugs in cancer therapy.

Description:
CROSS-REFERENCE 
     This application claims the benefit of U.S. Provisional Application No. 61/150,031, filed Feb. 5, 2009, and which is incorporated herein by reference in its entirety 
    
    
     FIELD OF THE INVENTION 
     This invention provides novel prodrugs of steroidal CYP17 inhibitors for the treatment of urogenital and/or androgen-related cancers, diseases and/or conditions, including castrate-resistant prostrate cancer, the synthesis of these new chemical entities, and to methods of using the same in the treatment of urogenital and/or androgen-related cancers, diseases and/or conditions. 
     BACKGROUND OF THE INVENTION 
     Prostate cancer (PCA) is the most common malignancy and age-related cause of cancer death worldwide. Apart from lung cancer, PCA is the most common form of cancer in men, and the second leading cause of death in American men. In the United States in 2008, an estimated 186,320 new cases of prostate cancer were expected to be diagnosed and about 28,660 men were expected to die of this disease, with African American men and Jamaican men of African decent having the highest incidence rates thereof in the world (American Cancer Society—Cancer Facts and Figures 2008). 
     Androgens play an important role in the development, growth, and progression of PCA (McConnell, J. D.,  Urol. Clin. North Am.,  1991, 18: 1-13), with the two most important androgens in this regard being testosterone, 90% of which is synthesized in the testes and the remainder (10%) is synthesized by the adrenal glands, and the more potent androgen, dihydrotestosterone (DHT), to which testosterone is converted by the enzyme steroid, 5α-reductase, that is localized primarily in the prostate (Bruchovsky, N. et al.,  J. Biol. Chem.,  1968, 243, 2012-2021). 
     Huggins et al. introduced androgen deprivation as a therapy for advanced and metastatic PCA in 1941 (Huggins, C. et al.,  Arch. Surg.,  1941, 43, 209-212), and since then, androgen ablation therapy has been shown to produce the most beneficial responses in multiple settings in PCA patients (Denmeade, S. R. et al.,  Nature Rev. Cancer,  2002, 2: 389-396). Orchiectomy (either surgical, or medical with a GnRH agonist) remains the standard treatment option for most prostate cancer patients, reducing or eliminating androgen production by the testes, but not affecting androgen synthesis in the adrenal glands. Several studies have reported that a combination therapy of orchiectomy with antiandrogens to inhibit the action of adrenal androgens significantly prolongs the survival of PCA patients (Crawford, E. D. et al.,  New Engl. J. Med.,  1989, 321, 419-424; Crawford, E. D. et al.,  J. Urol.,  1992, 147: 417A; and Denis, L.,  Prostate,  1994, 5 (Suppl.), 17s-22s). 
     In a recent featured article by Mohler and colleagues (Mohler, J. L. et al.,  Clin. Cancer Res.,  2004, 10, 440-448) it was clearly demonstrated that testosterone and dihydrotestosterone occur in recurrent PCA tissues at levels sufficient to activate androgen receptors. In addition, using microarray-based profiling of isogenic PCA xenograft models, Sawyer and colleagues (Chen, C. D. et al.,  Nat. Med.,  2004, 10, 33-39) found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy. Potent and specific compounds that inhibit androgen synthesis in the testes, adrenals, and other tissue may therefore be a more effective for the treatment of PCA (Njar, V. C. O. and Brodie, A. M. H.,  Current Pharm. Design,  1999, 5: 163-180). 
     In the testes and adrenal glands, the last step in the biosynthesis of testosterone involves two key reactions that occur sequentially, both reactions being catalyzed by a single enzyme, the cytochrome P450 monooxygenase 17α-hydroxylase/ 17,20 -lyase (CYP17) (Hall, P. F.,  J. Steroid Biochem. Molec. Biol.,  1991, 40, 527-532). Ketoconazole, an antifungal agent that also inhibits P450 enzymes, is also a modest CYP17 inhibitor, and has been used clinically for the treatment of PCA (Trachtenberg, J. et al.,  J. Urol.  1983, 130, 152-153). It has been reported that careful scheduling of treatment can produce prolonged responses in otherwise castrate-resistant prostate cancer patients (Muscato, J. J. et al.,  Proc. Am. Assoc. Cancer Res.,  1994, 13: 22 (Abstract)). Further, ketoconazole was found to retain activity in advanced PCA patients with progression, despite flutamide withdrawal (Small, E. J. et al.,  J. Urol.,  1997, 157, 1204-1207), and although the drug has now been withdrawn from use because of liver toxicity and other side effects, the ketoconazole results suggest that more potent and selective inhibitors of CYP17 could provide useful agents for treating this disease, even in advanced stages, and in some patients who may appear to be hormone refractory. 
     A variety of potent steroidal and non-steroidal inhibitors of CYP17 have been reported, some of which having been shown to be potent inhibitors of testosterone production in rodent models (Njar and Brodie, op. cit.). Recently, Jarman and colleagues have described the hormonal impact of their most potent CYP17 inhibitor, abiraterone, in patients with prostate cancer (O&#39;Donnell, A. et al.,  Br. J. Cancer,  2004, 90: 2317-2325). Some potent CYP17 inhibitors have been shown to also inhibit 5α-reductase and/or be potent antiandrogens with potent antitumor activity in animal models (Njar and Brodie, op. cit., and Long, B. J. et al.,  Cancer Res.,  2000, 60, 6630-6640). 
     In addition to abiratcronc and to related publications from Barrie and Jarman, Njar et al. disclosed a series of potent CYP17 inhibitors/antiandrogens, the 17-benzazoles, 17-pyrimdinoazoles and 17-diazines in Published International Patent Application WO2006/093993 (University of Maryland). These compounds are potent inhibitors of human CYP17 enzyme, as well as potent antagonists of both wild type and mutant androgen receptors (AR). Particularly-potent CYP17 inhibitors included 3-β-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (Compound 5), 17-(1H-benzimidazole-1-yl)androsta-4,16-diene-3-one (Compound 6), and 3-β-hydroxy-17-(5′-pyrimidyl)androsta-5,16-diene (Compound 15), with IC 50  values of 300, 915 and 500 nM, respectively. 
     
       
                 
         
             
             
         
      
     
     Compounds 5, 6, and 15 were effective at competing with the binding of  3 H-R1881 (methyltrienolone, a stable synthetic androgen) to both the mutant LNCaP A and the wild-type AR, with a 2.2- to 5-fold higher binding efficiency to the latter. Compounds 5 and 6 were also shown to be potent pure AR antagonists, with cell-growth studies showing that Compounds 5 and 6 inhibit the growth of DHT-stimulated LNCaP and LAPC4 prostate cancer cells with IC 50  values in the low micromolar range (i.e., &lt;10 μM). Their inhibitory potencies were comparable to that of casodex, but remarkably superior to that of flutamide. 
     The pharmacokinetics of compounds 5 and 6 in mice showed that following s.c. administration of 50 mg/kg of compounds 5 and 6, peak plasma levels of 16.82 and 5.15 ng/mL, respectively, occurred after 30 to 60 minutes, both compounds were cleared rapidly from plasma (terminal half-lives of 44.17 and 39.93 minutes, respectively), and neither was detectable at 8 hours. Compound 5 was rapidly converted into a metabolite, tentatively identified as 17-(1H-benzimidazol-1-yl)androsta-3-one. 
     When tested in vivo, compound 5 proved to be very effective at inhibiting the growth of androgen-dependent LAPC4 human prostate tumor xenograft, while compound 6 proved to be ineffective. Administration of compound 5 (50 mg/kg, twice daily) resulted in a 93.8% reduction (P=0.00065) in the mean final tumor volume compared with controls, and it was also significantly more effective than castration. This was the first example of an anti-hormonal agent (an inhibitor of androgen synthesis (CYP17 inhibitor)/antiandrogen) that is significantly more effective than castration in suppression of androgen-dependent prostate tumor growth. In view of these impressive anti-cancer properties, compound 5 and analogs may be used for the treatment of human prostate cancer, as well as breast cancer, ovarian cancer, and other urogenital cancers or other androgen-related conditions or diseases. 
     In addition to a compound&#39;s efficacy, oral bioavailability is also often an important consideration for the development of molecules as therapeutic agents. The calculated physical properties of Compound 5, for example, satisfies both the Lipinski “rule of five” (Lipinski, C. A.,  J Pharmacol Toxicol Methods  2000, 44, (1), 235-49) and the recently-proposed rule by Veber et al. (Veber, D. F. et al.,  J Med Chem  2002, 45, (12), 2615-23) for predicting an improved likelihood of high or drug-like oral bioavailability for new drug candidates, as presented for Compound 5 in Table 1. These data suggest that the compound should be orally bioavailable and, as such, a strong drug candidate. 
     
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Molecular Properties of Compound 5 (VN/124-1) 
               
               
                 Based on Lipinski&#39;s and Verber&#39;s Criteria 
               
             
          
           
               
                   
                 Limit 
                 VN/124-1 
                 Results 
               
               
                   
                   
               
             
          
           
               
                 A. Lipinski Criterion 
                   
                   
                   
               
               
                 Hydrogen bond donors 
                 ≦5 
                 1 
                 Pass 
               
               
                 Hydrogen bond acceptors 
                 ≦10 
                 2 
                 Pass 
               
               
                 Molecular weight 
                 ≦500 
                 388.2515 
                 Pass 
               
               
                 CLogP 
                 &lt;5 
                 5.822 
                 Fail 
               
               
                 B. Veber&#39;s Criterion 
               
               
                 Number of rotatable bonds 
                 ≦10 
                 1 
                 Pass 
               
               
                 Polar surface area 
                 ≦140°A 2   
                 38.05°A 2   
                 Pass 
               
               
                 Sum of hydrogen bond donors and 
                 ≦12 
                 3 
                 Pass 
               
               
                 acceptors 
               
               
                   
               
             
          
         
       
     
     However, some initial studies have indicated that compound 5 has low (˜10%) oral bioavailability in rats. On the basis of the Lipinski&#39;s rule, compound 5 has a higher cLogP value (i.e., &gt;5), which could be the major reason for the finding of poor oral bioavailability, as is typical of many steroids. Because oral administrations of drugs are generally preferred, it is important to find ways to improve the oral bioavailability of steroids exemplified by compound 5, as well as the other compounds presented in WO2006/093993. 
     Additionally, modifications of a compound&#39;s structure, such that the serum half-life is extended and C max  is delayed, are desired, due to better dosing regimens and consistent delivery of the drug to the target in a single dosing. 
     Further background of the invention is contained in U.S. Pat. No. 5,604,213 (Barrie et al); U.S. Pat. No. 5,994,335 (Brodie et al); U.S. Pat. No. 6,200,965 (Brodie et al); and, U.S. Pat. No. 6,444,683 (Brodie et al). 
     Certain references cited herein are incorporated by reference in their entirety. 
     SUMMARY OF THE INVENTION 
     In some embodiments, the invention contemplates a compound of Formula I: 
                                
wherein:
 
     the ABC ring structure is optionally substituted independently at each position and wherein hydrogen substituents on adjacent carbon atoms of the ABC ring structure are optionally removed and replaced by a pi-bond between the adjacent carbon atoms; 
     Y is Z-L-C(═O)O—; and 
     either 
     X is an optionally substituted heterocycle that is a pyridine, pyrazine, pyrimidine, pyridazine, benzimidazole, benzotriazole, pyrimidinoimidazole, or pyrimidinotriazole group, wherein the benzimidazole, benzotriazole, pyrimidinoimidazole or pyrimidinotriazole group is bonded to the C17 position through a nitrogen atom on a 5-membered ring of the heterocycle, and the pyridine, pyrazine, pyrimidine, or pyridazine group is bonded to the C17 position through a carbon atom of the heterocycle; 
     L is C 1 -C 12 -alkyl, fluoro-C 2 -C 6 -alkyl, aryl, arylalkyl, alkylaryl, alkoxyalkyl, polyalkoxyalkyl, or heteroaryl, any of which is optionally cyclic or together with Z forms a ring, wherein L is optionally substituted with one or more of alkyl, arylalkyl, alkylaryl, alkylheteroaryl, halogen, hydroxyl, alkoxy, and mercaptan; and 
     Z is a charged group that is charged under normal physiological conditions, wherein the charged group is a sulfonic acid; a phosphonic acid; a fluoroalkanol; or an acidic hydroxyl group, 
     or 
     X is an optionally-substituted pyridine group; 
     L is C 1 -C 12 -alkyl, fluoro-C 2 -C 6 -alkyl, aryl, arylalkyl, alkylaryl, alkoxyalkyl, polyalkoxyalkyl, or heteroaryl, any of which is optionally cyclic or together with Z forms a ring, wherein L is optionally substituted with one or more of alkyl, arylalkyl, alkylaryl, alkylheteroaryl, halogen, hydroxyl, alkoxy, alkylamino, and mercaptan; and 
     Z is a charged group that is charged under normal physiological conditions, wherein the charged group is a quaternary ammonium group of the formula (R 3 N + )—, wherein each R group is independently C 1 -C 7 -branched alkyl, C 1 -C 7 -straight-chain alkyl, aryl, alkylaryl, aralkyl, heteroaryl, or two or more R groups together form a ring; a sulfonic acid; a phosphonic acid; a fluoroalkanol; or an acidic hydroxyl group, or a pharmaceutically-acceptable salt thereof. 
     In some embodiments, the invention contemplates a pharmaceutical composition comprising a therapeutically-effective amount of one or more compounds of the invention and one or more pharmaceutically-acceptable excipients, bulking agents, binders, flow agents, release agents, carriers or diluents. 
     In some embodiments, the invention contemplates a method of treating a cancer or a urogenital disease in a subject in need or want thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound of the invention. 
     In some embodiments, the invention contemplates a method of treating a cancer or a urogenital disease in a subject in need or want thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound of the invention, in combination with a hormone therapy, a chemotherapy, a radiation therapy, an immunotherapy, or surgery. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     As used herein, the following terms have the following definitions, unless otherwise specified. 
     Alkyl is a C 1 -C 12 -straight, C 1 -C 12 -branched, or C 3 -C 12 -cyclic group, optionally substituted independently at each position with one or more of hydroxyl, methoxy, ethoxy, sulfhydryl, methylmercapto, ethylmercapto, fluorine, chlorine, bromine, iodine, aryl, and heteroaryl. 
     Aryl is a mono- or poly-cyclic aromatic system. Non-limiting examples of aryl include phenyl, naphthyl, indenyl, fluorenyl, phenathrenyl, and azulenyl. Aryl is optionally substituted independently at each position with one or more of hydroxyl, methoxy, ethoxy, sulfhydryl, methylmercapto, ethylmercapto, fluorine, chlorine, bromine, iodine, oxo, and heteroaryl. In some embodiments, aryl groups contain from five to ten ring atoms. 
     Heteroaryl is a mono- or poly-cyclic aromatic system comprising at least one aromatic ring with at least one ring heteroatom, wherein the heteroatom is nitrogen, oxygen, or sulfur. Heteroaryl is optionally substituted independently at each position with hydroxyl, methoxy, ethoxy, sulfhydryl, methylmercapto, ethylmercapto, fluorine, chlorine, bromine, iodine, oxo and aryl. Non-limiting examples of heteroaryl groups include furan, thiophene, pyrrole, pyrrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine, indole, carbazole, benzofuran, benzothiphene, benzthiazole, indazole, quinoline, isoquinoline, cinnoline, and phthalazine. In some embodiments, heteroaryl groups contain from five to twelve ring atoms. 
     Alkylaryl is an alkyl group that is distally attached via an aryl group, for example, tolyl. 
     Aralkyl is an aryl group that is distally attached via an alkyl group, for example, benzyl. 
     Polyalkoxyl is polypropylene glycol) or poly(ethylene glycol), wherein the monomers are repeated 2-100 times, wherein such polyalkoxy groups may be defined by the precise range of repeating units (e.g., 35-40), by the targeted peak of envelope distribution in the repeating units (e.g., 114 from PEG5000), or by a selection for solubility or physical properties, and wherein such groups are optionally “capped” by an alkyl group (MPEG5000 for methoxy-PEG5000) or an aryl group, such as phenyl (polyalkoxylaryl). 
     Numbering of the steroid core as used herein is: 
     
       
                 
         
             
             
         
      
     
     The instant invention contemplates the use of prodrugs, (modified versions or precursors of a parent compound, designed to enhance delivery properties and be converted to the parent compound in the body in a predictable, consistent manner) to improve oral bioavailability and pharmacokinetics of effective therapeutic agents. The invention provides prodrugs of steroidal C-17 heterocycles, and methods of synthesizing and using the same to treat urogenital and/or androgen-related cancers, diseases and conditions. 
     In some embodiments, a prodrug of the invention comprises a prodrug group at the 3-carbon on the “A” ring of the compound. In some embodiments, the prodrug group comprises an ester linkage. In some embodiments, the prodrug group is attached to the A-ring by the ester linkage. In some embodiments, the prodrug group comprises a charged group. A charged group is a group that is charged under normal physiological conditions. Non-limiting examples of a charged group include trialkylammonium groups, quaternary ammonium groups, sulfonic acids, phosphonic acids, fluoroalkanols; or acidic hydroxyl groups. In some embodiments, an acidic hydroxyl group is made acidic by the resonance and/or inductive effect of a nearby electron-withdrawing group. In some embodiments, an acidic hydroxyl group is made acidic by the resonance and/or inductive effect of a nearby electron-withdrawing group, wherein the acidic hydroxyl group is more acidic than an analogous hydroxyl group lacking the nearby electron-withdrawing group. In some embodiments, the acidic hydroxyl group is more acidic than water. In some embodiments, the acidic hydroxyl group is phenolic. In some embodiments, the acidic hydroxyl group has a substantial negative charge in water. In some embodiments, the acidic hydroxyl group exists substantially as an alkoxide in water. In some embodiments, the acidic hydroxyl group has a substantial negative charge in physiological fluids. In some embodiments, the acidic hydroxyl group has a substantial negative charge under normal physiological conditions. In some embodiments, the acidic hydroxyl group exists substantially as an alkoxide under normal physiological conditions. In some embodiments, normal physiological conditions are conditions inherent in a living organism. 
     In some embodiments, the charged group is connected to the ester linkage by a linking group. In some embodiments, the linking group is C 1 -C 12 -alkyl, fluoro-C 2 -C 6 -alkyl, aryl, arylalkyl, alkylaryl, alkoxyalkyl, polyalkoxyalkyl, or heteroaryl. In some embodiments, the linking group is cyclic. In some embodiments, the linking group together with the charged group forms a ring. In some embodiments, the linking group is optionally substituted with one or more of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, halogen, hydroxyl, alkoxy, alkylamino, and mercaptan. 
     In some embodiments, the prodrug group is a quaternary ammonium species, for example, betaine, carnitine, and cocamidopropylbetaine (CAPB). In some embodiments, the prodrug group is an oxycarbonylalkylphosphonate; an oxycarbonylalkylsulfonate; or a phenolic carboxylate, such as syringic acid or gallic acid, or a pharmaceutically-acceptable salt of any such compound. The invention also contemplates synthetic analogs of these compounds. In some embodiments, the synthetic analog has improved bioavailability. In some embodiments, the synthetic analog has improved pharmacokinetics. In some embodiments, the prodrug group fragments in vivo to provide a drug. 
     In some embodiments, a prodrug fragments under a set of physiological conditions. In some embodiments, the set of physiological conditions that fragment a prodrug is general. In some embodiments, the set physiological conditions that fragment a prodrug is specific to the identity of the prodrug. In some embodiments, the set of physiological conditions comprises pH. In some embodiments, the set of physiological conditions comprises temperature. In some embodiments, the set of physiological conditions comprises metabolism. In some embodiments, the set of physiological conditions comprises hydrolysis. In some embodiments, the set of physiological conditions comprises catalysis. In some embodiments, the set of physiological conditions comprises enzyme activity. In some embodiments, the set of physiological conditions comprises oxidation or reduction. 
     In some embodiments, the optional substitution for the ABC ring structure includes one or more of: C 1 -C 6 -alkyl; halogenated C 1 -C 6 -alkyl; C 1 -C 6 -alkenyl; halogenated C 1 -C 6 -alkenyl; halogen; amino; aminoalkylene; hydroxyimino; and hydroxy. In some embodiments, an alkenyl group is bonded to the ABC ring structure by an sp 3  carbon of the alkenyl group. In some embodiments, an alkenyl group is bonded to the ABC ring structure by an sp 2  carbon of the alkenyl group. In some embodiments, hydrogen substituents on adjacent carbon atoms of the ABC ring structure are removed and replaced by a pi-bond between the adjacent carbon atoms. 
     In some embodiments, the pyridine, pyrazine, pyrimidine, pyridazine, benzimidazole, benzotriazole, pyrimidinoimidazole, or pyrimidinotriazole functionalities attached to the D ring are optionally substituted with one or more of halogen, amino, aminoalkylene, hydroxy, —SH, —S—C 1 -C 6 -alkyl, C 1 -C 6 -alkyl and halogenated C 1 -C 6 -alkyl. 
     In some embodiments, the pyridine, pyrazine, pyrimidine, pyridazine, benzimidazole, benzotriazole, pyrimidinoimidazole, and pyrimidinotriazole groups are, respectively: 
     
       
                 
         
             
             
         
      
     
     In one embodiment, the C ring substitution consists of the C13 methyl group. 
     In some embodiments, the compound is one of the following: 
     
       
                 
         
             
             
         
      
     
     The ability of compound 5 and abiraterone to inhibit CYP 17 and steroid 5a-reductases, the binding to and transactivation of androgen receptors, and the antiproliferative effects against two human prostate cancer cell lines, LNCaP and LAPC-4, were studied and reported in WO2006/093993 and in Potter et al. (Potter, G. A. et al.,  J. Med. Chem.,  1995, 38, 2463-2471). WO2006/093993 also reported the evaluation of the pharmacokinetics of Compounds 5 and 6 of Scheme 1 in mice and the in vivo antitumor activities against human LAPC-4 prostate carcinoma in mice. 
     In one embodiment, the prodrug of this invention includes a pharmaceutically-acceptable prodrug group. In some embodiments, the prodrug group is attached to the drug via one or more bonds that are labile under normal physiological conditions. In some embodiments, the prodrug group provides improved oral bioavailability and pharmacokinetics over the drug. In some embodiments, the prodrug group is incorporated at the Y position of a compound of Formula I. 
     In some embodiments, the compound of Formula I is: 
                                
wherein R 1  is H, alkyl, alkylaryl, mercaptoalkyl, hydroxyalkyl, arylalkyl, alkylamino, aminoalkyl, alkylcarboxyl, carboxyalkyl, alkylamido, amidoalkyl, or other group derived from natural or unnatural amino acids; R is independently at each occurrence C 1 -C 5 -alkyl, hydroxyalkyl, phenyl, pyridyl, benzyl or alkoxyalkyl, wherein each R group may or may not be joined to another R group to form a ring; and n is from 1-50, or a stereoisomer or pharmaceutically-acceptable salt thereof. In some embodiments, a value for n is selected for improved pharmacokinetic properties.
 
     In some embodiments, the compound of Formula I is: 
     
       
                 
         
             
             
         
      
     
     In some embodiments, the substitution of the prodrug group is modified to adjust the pKa of the prodrug. In some embodiments, the substitution of the prodrug group is modified to adjust the pKa of the prodrug such that the prodrug exists in a charged state at the desired point of adsorption, distribution, metabolism and/or excretion. 
     In some embodiments, the compound of Formula I is: 
     
       
                 
         
             
             
         
      
     
     In some embodiments, the substitution of the prodrug group is modified to adjust the pKa of the prodrug. In some embodiments, the substitution of the prodrug group is modified to adjust the pKa of the prodrug such that the prodrug exists in a charged state at the desired point of adsorption, distribution, metabolism and/or excretion. 
     In some embodiments, the compound of Formula I is: 
                                
wherein n is from 0 to 50. In some embodiments, a value of n is chosen such that the pKa of the fluoroalkanol is within physiological range.
 
     In some embodiments, the compound of Formula I is: 
                                
wherein n is from 0 to 50. In some embodiments, a value of n is chosen such that the pKa of the fluoroalkanol is within physiological range.
 
     Some embodiments contemplate pharmaceutically-acceptable salts of the invention. Pharmaceutically-acceptable salts of the compounds of the invention are generated, for example, by treating the compounds of the invention with an acid, a hemi-acid, or a salt to afford the corresponding salt form. Non-limiting examples of pharmaceutically-acceptable salts include chlorides, bromides, iodides, phosphates, sulfates, carbonates, bicarbonates, formates, acetates, propionates, benzoates, picolinates, fumarates, maleates, malates, succinates, methanesulfonates, toluenesulfonates, mesitylenesulfonates, trifluoromethanesulfonates, tetrafluoroborates, tetraphenylborates, and hexafluorophosphates. 
     Exemplary Compound Preparation 
     The preparation of 17-benzazoles and 17-diazines is outlined herein, with these methods being applicable, analogously, to other analogs described herein. 
     The key intermediate in the synthesis of the 17-benzazole, 3β-acetoxy-17-chloro-16-formylandtrosta-5,16-diene (2), was obtained by the routine procedure as previously described (Njar, V. C. O. et al.,  Bioorg. Med. Chem. Lett.,  1996, 6, 2777-2782, and Njar, V. C. O. et al,  J. Med. Chem.,  1998, 41, 902-912). Treatment of Compound 2 with benzimidazole in the presence of K 2 CO 3  in DMF at approx. 80° C. gave the desired 3β-acetoxy-17-1H-benzimidazole (3) in near quantitative yield. Compound 3 was smoothly deformylated with 10% palladium on activated charcoal in N-methylpyrrolidinone to give Compound 4 in 93% yield, from which hydrolysis gave the required 3β-hydroxy-17-benzimidazole (5): 
     
       
                 
         
             
             
         
      
     
     Modified Oppenauer oxidation of Compound 5 afforded the corresponding Δ 4 -3-oxo analog (6). 
     The reaction of Compound 2 with benzotriazole in the presence of K 2 CO 3  in DMF at approximately 80° C. gave the desired 3β-acetoxy-17-benzo-1H-1,2,3-triazole (7b) in excellent yield, together with the 2H-1,2,3-triazole regioisomer (7a) in approximately 5% yield. These two regioisomers were readily separated by flash column chromatography (FCC) on silica gel, and were easily identified by their respective proton NMR spectra. Thus, the four aromatic protons of the symmetrical 2H-1,2,3-triazole (7a) appeared as two pairs of doublets at δ 7.43, 7.45, 7.88 and 7.90, while the four aromatic protons of the unsymmetrical 1H-1,2,3-triazole (7b) appeared as a multiplet at δ 7.46 (2H) and doublets at δ 7.57 (1H) and 8.15 (1H), respectively. In addition, the 16-CHO proton in Compound 7a was significantly shifted downfield to δ 10.66 compared to that in Compound 7b at δ 9.59. Deformylation of Compound 7b with in situ generation of Rh(1,3-bis(diphenylphosphino)propane) 2   + Cl −  catalyst [Rh(dppp) 2   + Cl − ] in refluxing xylenes gave compound 8, and hydrolysis of the 3β-acetoxy group afforded the target 3β-hydroxy-17-(benzo-1H-1,2,3-triazol-1-yl)androsta-5,16-diene (9) in 90% yield. 
     
       
                 
         
             
             
         
      
     
     Synthesis of the 17-diazines, 17-diazine (14) and 17-pyrimidine (15), commenced from the readily-available dehydroepiandrosterone (Compound 11), which was converted to the corresponding 17-hydrazone (12) by treatment with hydrazine hydrate and hydrazine sulfate, as previously described by Potter et al. (Potter, G. A. et al.,  Org. Prep. Proc. Int.,  1997, 29, 123-1280). Treatment of Compound 12 with iodine in the presence of 1,1,3,3-tetramethylguanidine gave the vinyl 17-iodide (13) in excellent yield. The palladium-catalyzed cross-coupling reactions (Choshi, T. et al.,  J. Org. Chem.,  1995, 60, 5899-5904) of Compound 13 with (2-tributylstannyl)pyrazine or (5-tributylstannyl)pyrimidine proceeded to give 3β-hydroxy-17-(2-pyrazyl)-androsta-5,16-diene (14, 15%), and 3β-hydroxy-17-(5-pyrimidyl)-androsta-5,16-diene (15, 10%), respectively. 
     
       
                 
         
             
             
         
      
     
     The identity of the target Compounds 14 and 15 were readily confirmed by their proton NMR spectra: the three nonequivalent protons of the 17-pyrazine moiety in Compound 14 appearing as three singlets at δ 8.35, 8.48 and 8.70, while the three protons of the 17-pyrimidine moiety in Compound 15 appearing as two singlets at δ 8.73 (2H) and δ 9.07 (1H). Further, the 17-diazine groups of Compounds 14 and 15 exhibit different influences on the chemical shifts of the corresponding 16-olefinic protons with respect to that of the precursor Δ 16 -17-iodide 13: the 16-H in Compound 14 appearing as a singlet at δ 6.77, being significantly deshielded compared to the 16-H in Compound 13 (δ 6.14); and the 16-H in Compound 15 appearing at δ 6.11, similar to Compound 13. Compound 15 has been reported previously by Haidar et al (Haidar, S. et al.,  Arch. Pharm. Med. Chem.,  2001, 334, 373-374) and its biological and pharmacological activities have also been described (Haidar, S. et al.,  J. Steroid Biochem. Molec. Biol.,  2003, 84, 555-562). 
     Abiraterone may be prepared as described in the literature (Potter, G. A. et al.,  J. Med. Chem ., op. cit.). 
     Synthesis of the disclosed prodrugs is illustrated herein, with the understanding that the examples provided can be applied to all compounds contemplated by the instant disclosure. 
     The present invention also provides pharmaceutical compositions comprising a pharmaceutically-acceptable carrier and one or more of the compounds disclosed herein. Suitable pharmaceutically-acceptable carriers include, for example, vehicles, adjuvants, excipients, and diluents. 
     The present invention also provides methods of treating urogenital and/or androgen-related cancers, diseases and/or conditions, including, without limitation, breast cancer, prostate cancer (e.g., prostatic adenocarcinoma), other urogenital cancers, prostate hyperplasia (BPH), and/or other androgen-related diseases and/or conditions, by administering to a subject in need or want thereof a therapeutically-effective amount of a compound of the present invention. The treatment may be prophylactic (referring to any degree of inhibition of the onset of a cellular disorder, including complete inhibition, such as in a subject expected to soon exhibit the cellular disorder) or therapeutic (referring to any degree of inhibition or any degree of beneficial effects on the disorder or condition in the subject (e.g., human), (e.g., inhibition of the growth or metastasis of a tumor or circulating tumor cells). Maintenance therapy, in which continued suppression of symptoms or progression of disease is achieved by continued administration of the compound, is also contemplated by this invention. Examples of prostate diseases that can be treated include, e.g., prostatic hyperplasia (BPH), and prostate cancer (e.g., prostatic adenocarcinoma). 
     Non-limiting examples of cancer symptoms include: tumors, persistent cough, bloody saliva, changes in bowel habits, bloody stool, anemia, lumps including lumps of the breast or testicle, bodily discharges, changes in urinary habits, pain or burning upon urination, prostate enlargement, bloody urine, swollen glands, warts, moles, genital bleeding, involuntary weight gain or loss, persistent itching, persistent skin discoloration, non-healing sores, headaches, pain or discomfort such as in the back or pelvis, cramps such as abdominal cramps, weakness, and loss of appetite. 
     Methods of administering a compound of the present invention to a subject, for example, a mammal, such as a rat, rabbit, dog or human, are known in the art. Although more than one route may be used to administer a particular composition, a particular route can provide a more immediate and more effective result than another route. 
     In some embodiments, a pharmaceutical composition is formulated for oral administration. In some embodiments, the composition comprises a suspension of a compound in a suitable vehicle. Non-limiting examples of vehicles for oral administration include phosphate-buffered saline (PBS), 5% dextrose in water (D5W), 1% carboxymethyl cellulose (CMC) and a syrup. In some embodiments, a composition is formulated to stabilize the consistency of a dose over a period of storage and administration. In some embodiments, the composition comprises a solution. In some embodiments, a solution comprises an effective amount of one or more compounds dissolved in a diluent. Non-limiting examples of diluents include water, saline, and buffers. In some embodiments, the composition comprises a solid dosage form. In some embodiments, the solid dosage form comprises a capsule, a caplet, a lozenge, a sachet, or a tablet. In some embodiments, the solid dosage form is a liquid-filled dosage form. In some embodiments, the solid dosage form is a solid-filled dosage form. In some embodiments, the solid dosage form is a solid-filled tablet, capsule, or caplet. In some embodiments, the solid-filled dosage form is a powder-filled dosage form. In some embodiments, the solid dosage form comprises a compound in the form of micronized particles, solids or granules. In some embodiments, the composition comprises an emulsion. In some embodiments, the emulsion comprises a compound of the invention characterized by surfactant properties. 
     In some embodiments, the solid dosage form comprises one or more of lactose, sorbitol, maltitol, mannitol, cornstarch, potato starch, microcrystalline cellulose, hydroxypropyl cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, pharmaceutically-acceptable excipients, colorants, diluents, buffering agents, moistening agents, preservatives, flavoring agents, carriers, and binders. In some embodiments, the solid dosage form comprises one or more materials that facilitate manufacturing, processing or stability of the solid dosage form. In some embodiments, a lozenge comprises a flavoring agent. Non-limiting examples of excipients useful in the present invention include sucrose, gum acacia, gum tragacanth, a pastille, an inert base, a gelatin, glycerin, a sucrose emulsion, an acacia emulsion, and a gel. In some embodiments, a solid dosage form is coated. In some embodiments, the coating improves absorption of the compound in the gastrointestinal tract. Non-limiting examples of coatings include cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (CVAP), and modified coatings thereof. 
     In some embodiments, the composition is formulated as an aerosol. In some embodiments, the aerosol is administered via inhalation. In some embodiments, the aerosol comprises one or more propellants. Non-limiting examples of propellants include dichlorodifluoromethane, hydrofluorocarbon (such as HFC 134a and/or 227), and nitrogen. 
     In some embodiments, a compound is administered by a route that is oral, parenteral, enteral, intraperitoneal, topical, transdermal, ophthalmic, nasal, local, non-oral, aerosol, spray, inhalation, subcutaneous, intravenous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, or intrathecal. In some embodiments, a dose is administered by a route that is oral, parenteral, enteral, intraperitoneal, topical, transdermal, ophthalmic, nasal, local, non-oral, aerosol, spray, inhalation, subcutaneous, intravenous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, or intrathecal. In some embodiments, the compound is administered as a suspension in PBS, D5W, or a carbohydrate-based syrup. 
     In some embodiments, the dose is administered as a suspension in PBS, D5W, or a carbohydrate-based syrup. 
     In some embodiments, a dose administered to a subject is an effective dose. In some embodiments, the effective dose provides a therapeutic response in the subject within a therapeutically-useful time frame. In some embodiments, the effective dose comprises a therapeutically-effective amount of a compound. In some embodiments, the therapeutically-effective amount provides a therapeutic response in the subject within a therapeutically-useful time frame. The specific dose level and frequency of dosage are influenced by a variety of factors, including the activity, metabolic stability, bioavailability, rate of excretion, biological half-life, and mode and time of administration of the compound; the age, body weight, health condition, gender, diet, and physical and health characteristics of the subject; and the severity of the cancer or other disease or condition. 
     Any effective amount of the compound may be administered. In some embodiments, a dose comprises an effective amount of a compound. In some embodiments, a dose is administered once a day. In some embodiments, a dose is administered more than once a day. In some embodiments, a dose is greater than about 1 mg/day. In some embodiments, a dose is greater than about 5 mg/day. In some embodiments, a dose is greater than about 10 mg/day. In some embodiments, a dose is greater than about 25 mg/day. In some embodiments, a dose is greater than about 50 mg/day. In some embodiments, a dose is greater than about 100 mg/day. In some embodiments, a dose is less than about 5000 mg/day. In some embodiments, a dose is less than about 4000 mg/day. In some embodiments, a dose is less than about 3000 mg/day. In some embodiments, a dose is less than about 2500 mg/day. In some embodiments, a dose is less than about 2000 mg/day. In some embodiments, a dose is less than about 1500 mg/day. In some embodiments, a dose is less than about 1000 mg/day. In some embodiments, a dose is less than about 500 mg/day. In some embodiments, a dose is from about 500 mg to about 1200 mg per day. In some embodiments, a dose is from about 500 mg to about 1500 mg per day. In some embodiments, a dose is from about 1 mg to about 5000 mg per day. In some embodiments, a dose is from about 5 mg to about 4000 mg per day. In some embodiments, a dose is from about 10 mg to about 3000 mg per day. In some embodiments, a dose is from about 25 mg to about 2000 mg per day. In some embodiments, a dose is from about 50 mg to about 2500 mg per day. In some embodiments, a dose is from about 100 mg to about 2000 mg per day. In some embodiments, a dose is from about 100 mg to about 1000 mg per day. In some embodiments, a dose is from about 100 mg to about 500 mg per day. 
     In one embodiment, a dose is about 0.01 to about 100 mg/kg of subject body mass per day. In some embodiments, a dose is about 0.05 to about 50 mg/kg of subject body mass per day. In some embodiments, a dose is about 0.1 to about 40 mg/kg of subject body mass per day. In some embodiments, a dose is about 0.25 to about 30 mg/kg of subject body mass per day. In some embodiments, a dose is about 0.5 to about 20 mg/kg of subject body mass per day. In some embodiments, a dose is about 0.75 to about 15 mg/kg of subject body mass per day. In some embodiments, a dose is about 1 to about 10 mg/kg of subject body mass per day. In some embodiments, a dose is about 2 to about 5 mg/kg of subject body mass per day. 
     In some embodiments, a composition has a concentration of greater than about 0.01% of the compound by mass. In some embodiments, a composition has a concentration of greater than about 0.025% of the compound by mass. In some embodiments, a composition has a concentration of greater than about 0.05% of the compound by mass. In some embodiments, a composition has a concentration of greater than about 0.075% of the compound by mass. In some embodiments, a composition has a concentration of greater than about 0.1% of the compound by mass. In some embodiments, a composition has a concentration of less than about 25% of the compound by mass. In some embodiments, a composition has a concentration of less than about 20% of the compound by mass. In some embodiments, a composition has a concentration of less than about 15% of the compound by mass. In some embodiments, a composition has a concentration of less than about 10% of the compound by mass. In some embodiments, a composition has a concentration of less than about 7.5% of the compound by mass. In some embodiments, a composition has a concentration of less than about 5% of the compound by mass. In some embodiments, a composition has a concentration of less than about 3% of the compound by mass. In some embodiments, a composition has a concentration of about 0.01% to about 25% of the compound by mass. In some embodiments, a composition has a concentration of about 0.025% to about 20% of the compound by mass. In some embodiments, a composition has a concentration of about 0.05% to about 15% of the compound by mass. In some embodiments, a composition has a concentration of about 0.02% to about 5% of the compound by mass. In some embodiments, a composition has a concentration of about 0.1% to about 3% of the compound by mass. In some embodiments, a composition has a concentration of about 10% to about 80% of the compound by mass. 
     In some embodiments, a compound of the invention is administered alone. In some embodiments, a compound is administered with one or more other ingredient(s), for example, a pharmaceutically-acceptable excipient, carrier or diluent. In some embodiments, a compound is used in combination with other cancer treatments. In some embodiments, the compounds of this invention are used as a part of or in combination with known cancer treatments, for example, hormone therapy, chemotherapy, radiation therapy, immunotherapy, and/or surgery. In one embodiment, one or more compounds are used in combination with one or more additional agents. In some embodiments, the additional agent is a drug. In some embodiments, the additional agent is a hormone. Non-limiting examples of drugs and/or hormones for use in combination with the prodrugs of this invention include anti-androgens such as flutamide and nilutamide; another CYP 17 inhibitor, such as abiraterone; luteinizing hormone-releasing hormone agonists, such as leuprolide, goserelin and buserelin; and drugs that prevent the adrenal glands from making androgens, such as ketoconazole and aminoglutethimide; and estrogens. Non-limiting examples of cancer drugs include cyclophosphamide, methotrexate, 5-fluorouracil (5-FU), doxorubicin, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, mechlorethamin, melphalan, procarbazine, bleomycin, doxorubicin, idarubicin mitoxantrone, chlorodeoxyadenosine, cytarabine, fludarabine, 6-mercaptopurine, methotrexate, 6-thioguanine, pentostatin, etoposide, gemcitabine, steroid creams, corticosteroids, prednisone, and dexamethasone. 
     Compounds of this invention may be administered to a subject at any time, as determined by the treating physician. In some embodiments, the compound is administered during one or more of Stage II, Stage III, and Stage IV of the cancer. In some embodiments, the compound is administered during an advanced stage of a urogenital and/or androgen-related disease or condition. 
     The embodiments of the disclosure are provided for the purpose of illustration, not limitation. 
     In some embodiments, the invention provides compound of Formula I: 
                                
wherein:
 
     the ABC ring structure is optionally substituted independently at each position and wherein hydrogen substituents on adjacent carbon atoms of the ABC ring structure are optionally removed and replaced by a pi-bond between the adjacent carbon atoms; 
     Y is Z-L-C(═O)O—; and 
     either 
     X is an optionally substituted heterocycle that is a pyridine, pyrazine, pyrimidine, pyridazine, benzimidazole, benzotriazole, pyrimidinoimidazole, or pyrimidinotriazole group, wherein the benzimidazole, benzotriazole, pyrimidinoimidazole or pyrimidinotriazole group is bonded to the C17 position through a nitrogen atom on a 5-membered ring of the heterocycle, and the pyridine, pyrazine, pyrimidine, or pyridazine group is bonded to the C17 position through a carbon atom of the heterocycle; 
     L is C 1 -C 12 -alkyl, fluoro-C 2 -C 6 -alkyl, aryl, arylalkyl, alkylaryl, alkoxyalkyl, polyalkoxyalkyl, or heteroaryl, any of which is optionally cyclic or together with Z forms a ring, wherein L is optionally substituted with one or more of alkyl, arylalkyl, alkylaryl, alkylheteroaryl, halogen, hydroxyl, alkoxy, and mercaptan; and 
     Z is a charged group that is charged under normal physiological conditions, wherein the charged group is a quaternary ammonium group of the formula (R 3 N + )—, wherein each R group is independently C 1 -C 7 -branched alkyl, C 1 -C 7 -straight-chain alkyl, aryl, alkylaryl, aralkyl, heteroaryl, or two or more R groups together form a ring; a sulfonic acid; a phosphonic acid; a fluoroalkanol; or an acidic hydroxyl group, 
     or a pharmaceutically-acceptable salt thereof. 
     or 
     X is an optionally-substituted pyridine group; 
     L is C 1 -C 12 -alkyl, fluoro-C 2 -C 6 -alkyl, aryl, arylalkyl, alkylaryl, alkoxyalkyl, polyalkoxyalkyl, or heteroaryl, any of which is optionally cyclic or together with Z forms a ring, wherein L is optionally substituted with one or more of alkyl, arylalkyl, alkylaryl, alkylheteroaryl, halogen, hydroxyl, alkoxy, alkylamino, and mercaptan; and 
     Z is a charged group that is charged under normal physiological conditions, wherein the charged group is a quaternary ammonium group of the formula (R 3 N + )—, wherein each R group is independently C 1 -C 7 -branched alkyl, C 1 -C 7 -straight-chain alkyl, aryl, alkylaryl, aralkyl, heteroaryl, or two or more R groups together form a ring; a sulfonic acid; a phosphonic acid; a fluoroalkanol; or an acidic hydroxyl group, 
     or a pharmaceutically-acceptable salt thereof. 
     In some embodiments, X is optionally substituted with one or more of halogen, amino, aminoalkylene, hydroxy, —SH, —S—C 1 -C 6 -alkyl, C 1 -C 6 -alkyl and halogenated C 1 -C 6 -alkyl. 
     In some embodiments, the pyridine, pyrazine, pyrimidine, pyridazine, benzimidazole, benzotriazole, pyrimidinoimidazole, and pyrimidinotriazole groups are, respectively: 
                                
wherein each * indicates a point of attachment to the C17 position.
 
     In some embodiments, the ABC ring structure is optionally substituted with one or more of C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, halogenated C 1 -C 6 -alkenyl, halogen, amino, aminoalkylene, hydroxyimino, and hydroxyl. 
     In some embodiments, Z is a quaternary ammonium group, wherein the quaternary ammonium group is trimethyl ammonium, triethyl ammonium, triphenyl ammonium, benzyldimethyl ammonium, benzyldiethyl ammonium, N-methylpiperidinium, N-ethylpiperidinium, or tribenzyl ammonium. 
     In some embodiments, Z is a sulfonic acid, and L is C 1 -C 6 -alkyl. 
     In some embodiments, Z is a phosphonic acid, and L is C 1 -C 6 -alkyl. 
     In some embodiments, the compound is: 
     
       
                 
         
             
             
         
      
     
     In some embodiments, the compound is: 
                                
wherein R is C 1 -C 6 -alkyl, aryl, heteroaryl, arylalkyl, or alkylaryl; R 1  is C 1 -C 8 -alkyl, aryl, aralkyl, alkylaryl, or alkylheteroaryl; and n is from 1 to 49.
 
     In some embodiments, the invention provides a pharmaceutical composition comprising a therapeutically-effective amount of one or more compounds of the invention and one or more pharmaceutically-acceptable excipients, bulking agents, binders, flow agents, release agents, carriers or diluents. 
     In some embodiments, the composition is an oral dosage form. 
     In some embodiments, the oral dosage form is a tablet, a caplet, a capsule or a liquid suspension. 
     In some embodiments, the amount of the compound is less than about 1000 mg. In some embodiments, the amount of the compound is less than about 2000 mg. 
     In some embodiments, the amount of the compound is from about 100 mg to about 500 mg. In some embodiments, the amount of the compound is from about 500 mg to about 1500 mg. 
     In some embodiments, the compound is: 
                                
wherein R is C 1 -C 6 -alkyl, aryl, heteroaryl, arylalkyl, or alkylaryl; and R 1  is C 1 -C 8 -alkyl, aryl, aralkyl, alkylaryl, or alkylheteroaryl; and n is from 1 to 49.
 
     In some embodiments, the invention provides a method of treating a cancer or a urogenital disease in a subject in need or want thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound of the invention. 
     In some embodiments, the cancer is a urogenital and/or androgen-related cancer. 
     In some embodiments, the cancer or urogenital disease is prostate cancer, breast cancer, ovarian cancer, other urogenital cancer, or prostate hyperplasia. 
     In some embodiments, the method further comprises administering to the subject a therapeutically-effective amount of one or more of an anti-androgen, a CYP17 inhibitor, a luteinizing hormone-releasing hormone agonist, a drug for preventing androgen production, an estrogen, and a chemotherapy drug. 
     In some embodiments, the amount is less than about 1000 mg. In some embodiments, the amount is less than about 2000 mg. 
     In some embodiments, the amount is from about 100 to about 500 mg. In some embodiments, the amount is from about 500 to about 1500 mg. 
     In some embodiments, the compound is: 
                                
wherein R is C 1 -C 6 -alkyl, aryl, heteroaryl, arylalkyl, or alkylaryl; and R 1  is C 1 -C 8 -alkyl, aryl, aralkyl, alkylaryl, or alkylheteroaryl; and n is from 1 to 49.
 
     In some embodiments, the invention provides a method of treating a cancer or a urogenital disease in a subject in need or want thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound of the invention, in combination with a hormone therapy, a chemotherapy, a radiation therapy, an immunotherapy, or surgery. 
     In some embodiments, the cancer comprises a urogenital and/or androgen-related cancer. 
     In some embodiments, the cancer or urogenital disease is prostate cancer, breast cancer, ovarian cancer, other urogenital cancer, or prostate hyperplasia. 
     In some embodiments, the amount is less than about 1000 mg. In some embodiments, the amount is less than about 2000 mg. 
     In some embodiments, the amount is from about 100 to about 500 mg. In some embodiments, the amount is from about 500 to about 1500 mg. 
     In some embodiments, the compound is: 
     
       
                 
         
             
             
         
      
     
     wherein R is C 1 -C 6 -alkyl, aryl, heteroaryl, arylalkyl, or alkylaryl; and R 1  is C 1 -C 8 -alkyl, aryl, aralkyl, alkylaryl, or alkylheteroaryl; and n is from 1 to 49. 
     EXAMPLES 
     Example 1 
     Betaine Ester of Abiraterone 
     
       
                 
         
             
             
         
      
     
     A solution of bromoacetic acid (3.0 mmol 417 mg) in dichloromethane (10 mL) is stirred while dicyclohexylcarbodiimide (3.0 mmol, 619 mg), dimethylaminopyridine (0.5 mmol, 61 mg), followed by a solution of abiraterone (2.9 mmol, 1.08 g) in dichloromethane (3 mL) are added. The resultant mixture is stirred at room temperature for four hours. The mixture is filtered to remove precipitated dicyclohexyl urea, and poured into ethyl acetate. The organic layers are washed (1N HCL, 5% sat&#39;d NaHCO 3 ), dried (brine, MgSO 4 ), and concentrated, with purification by column chromatography affording the pure alpha-halo ester. 
     The above-prepared bromoester (1.5 mmol, 743 mg) is dissolved in acetone (10 mL) and triethylamine (2.5 mmol, 253 mg, 350 μL) is added. The mixture is stirred until the steroid starting material is shown to be exhausted by TLC. The reaction mixture is concentrated in vacuo, and the residue is purified by reversed-phase HPLC to afford pure triethylammonium acetate of abiraterone. 
     Alternately, the above prepared bromoester (1.5 mmol, 743 mg) is dissolved in acetone (10 mL) and trimethylamine (2.5 mmol, 148 mg, 232 μL) is added. The mixture is stirred until the steroid starting material is shown to be exhausted by TLC, then concentrated in vacuo, and the residue is purified by reversed-phase HPLC to afford pure trimethylammonium acetate of abiraterone. 
     Example 2 
     Carnitine Ester of Abiraterone 
     
       
                 
         
             
             
         
      
     
     A solution of R-dimethylmalate (10 mmol, 1.62 g) in THF (40 mL) is cooled at −78° C. and stirred while borane-dimethylsulfide complex (9.5 mmol, 4.75 mL of a 2.0M solution) in THF is added. The mixture is allowed to warm to room temperature and stirred while heating at reflux until exhaustion of the starting diester is indicated by TLC. The reaction mixture is quenched by slow addition of THF-water (1:1, 10 mL), and the resulting mixture is carefully poured into a solution of sodium hydroxide (5M, 10 mL), and stirred overnight. The reaction mixture is concentrated in vacuo, and the residue is taken up into ethyl acetate (50 mL). The organic layer is washed (1N, HCl, 5% sat&#39;d aq NaHCO 3 ), dried (brine, MgSO 4 ), and concentrated in vacuo, with the residue being distilled in vacuo to afford purified methyl R-3,4-dihydroxybutyrate, or the residue may be used directly in the following step. 
     A solution of methyl R-3,4-dihydroxybutryate (6 mmol, 804 mg) in dry DMF (12 mL) is stirred at room temperature while tert-butyldimethylsilyl chloride (13.2 mmol, 996 mg) and imidazole (16 mmol, 545 mg) are added alternately in portions. The resultant mixture is stirred at room temperature for three hours, and is poured into a mixture of ethyl acetate (100 mL) and water. The aqueous phase is separated, and extracted with ethyl acetate (50 mL), and the combined organics are dried (brine, MgSO 4 ), filtered and concentrated in vacuo to afford the crude bis-silyloxy ester. Distillation in vacuo using a kugelrohr oven affords the pure methyl R-3,4-bis(tert-butyldimethylsiloxy)butyrate. 
     The above-prepared protected ester (5 mmol, 1.81 g) is dissolved in THF:water (4:1, 20 mL) and a solution of lithium hydroxide (10 mmol, 239 mg) in water (4 mL) is added. The reaction mixture is stirred until the ester is exhausted, as indicated by TLC, and poured into water, before the pH is adjusted to &lt;5 with HCl. The mixture is extracted with ethyl acetate (3×50 mL) and the combined organics are dried (brine, MgSO 4 ), and concentrated in vacuo to afford the crude acid, which is purified by reversed-phase HPLC, or column chromatography to afford the desired R-3,4-bis(tert-butyldimethylsilyloxy)butyric acid. 
     The protected acid is used in the preparation of an abiraterone prodrug. 
     
       
                 
         
             
             
         
      
     
     A solution of R-3,4-bis(tert-butyldimethylsilyloxy)butyric acid (1.0 mmol, 349 mmol), abiraterone (1.0 mmol, 374 mg) in dichloromethane (10 mL) is treated with EDC-HCl (1.0 mmol, 192 mg) and DMAP (0.1 mmol, 12 mg). The resultant mixture is stirred at room temperature for three hours, then poured into 1N HCl. The aqueous phase is separated, washed with dichloromethane (3×20 mL), and the combined organics are washed (3×50 mL 1N HCl, 1×50 mL 5% aq. NaHCO 3 ), dried (brine, MgSO 4 ), and concentrated, with the residue being purified by flash column chromatography (silica, EtOAc/hexanes elution) to afford the desired bis-protected ester. 
     The bis-silyl protected ester (0.5 mmol, 358 mg) is dissolved in THF (5 mL) and a solution of TBAF (1.0M in THF, 1.1 mL) is added. The solution is stirred for 2.5 hours, and is poured into water (10 mL). The aqueous phase is extracted with EtOAc (3×20 mL) and the combined organics are dried (brine, MgSO 4 ) and concentrated in vacuo, with the residue being purified by flash column chromatography (silica, EtOAc/hexanes elution) to afford the desired dihydroxy ester. 
     A solution of the R-3,4-dihydroxybutryl ester of abiraterone (0.5 mmol, 238 mg) in pyridine is treated with toluenesulfonyl chloride (0.5 mmol, 95 mg) and stirred for 24 hours at 4° C. The mixture is poured into ice-cold water (20 mL), and extracted with dichloromethane (3×50 mL). The combined organics are washed (3×1N HCl, 1×5% NaHCO 3 ), dried (brine, MgSO 4 ) and concentrated in vacuo (&lt;20° C.), with the residue being used directly in the following step. 
     The crude toluenesulfonate ester from the preceding step is dissolved in toluene (50 mL) and stirred, while trimethylamine (0.8 mmol, 47 mg, 74 μL) is added. The resultant mixture is heated for three hours, or until exhaustion of the toluenesulfonate ester is indicated by HPLC or TLC analysis. The resultant mixture is filtered and the solids washed with toluene. The R-3-hydroxy-4-trimethylammoniumbutyrate ester of abiraterone is purified via reversed-phase HPLC. 
     Example 3 
     Gallic Acid Ester of Abiraterone 
     
       
                 
         
             
             
         
      
     
     A solution of abiraterone (2 mmol, 747 mg), 3,4,5-tris[(tert-butyl dimethylsilyl)oxy]benzoic acid (2 mmol, 1.026 g), and 4-dimethylaminopyridine (1.0 mmol, 122 mg) in dichloromethane (10 mL) is stirred while dicyclohexylcarbodiimide (2.0 mmol, 412 mg) is added. The resultant suspension is stirred for three hours, and then filtered to remove precipitated dicyclohexylurea. The filtrate is washed with 1N HCl (2×50 mL), and the acid layers are extracted with dichloromethane (1×100 mL). The combined organics are dried (brine, MgSO 4 ), and concentrated in vacuo to afford a solid. The solid is purified by flash column chromatography (silica gel, CHCl 3 -MeOH) to afford the pure tris-silyl protected ester. 
     The above prepared ester is dissolved in THF (8 mL) and TBAF is added as a THF solution (1M, 6 mL, 6 mmol) and the resultant solution is stirred for two hours at room temperature. The mixture is poured into half-saturated aqueous sodium chloride and extracted with dichloromethane (2×100 mL). The combined organics are washed (1×1N HCl, 1× water), dried (brine, MgSO 4 ), and concentrated in vacuo to afford the crude gallic ester, which is purified by flash column chromatography (silica gel, CHCl 3 -MeOH) to afford the pure desired material. 
     Example 4 
     Phosphonoacetic Acid Ester of Abiraterone 
     
       
                 
         
             
             
         
      
     
     A mixture of phosphonoacetic acid (2 mmol, 280 mg), abiraterone (746 mg, 2 mmol) and 4-dimethylaminopyridine (2.5 eq, 305 mg) in dichloromethane (15 mL) is stirred while EDC-HCl (384 mg, 2.0 mmol) is added. The resultant mixture is stirred for eight hours at room temperature. The mixture is poured into 1N HCl (100 mL) and is extracted with dichloromethane (2×100 mL). The organic layers are combined, dried (brine, MgSO 4 ) and concentrated. The residue is purified by reversed-phase HPLC to afford the desired phosphonoacetic acid ester of abiraterone. 
     Example 5 
     Gallic Acid Ester of Compound 5 
     
       
                 
         
             
             
         
      
     
     A solution of compound 5 (2 mmol, 777 mg), 3,4,5-tris[(tert-butyl dimethylsilyl)oxy]benzoic acid (2 mmol, 1.026 g) 4-dimethylaminopyridine (1.0 mmol, 122 mg) in dichloromethane (10 mL) is stirred while dicyclohexylcarbodiimide (2.0 mmol, 412 mg) is added. The resultant suspension is stirred for three hours, and then filtered to remove precipitated dicyclohexylurea. The filtrate is washed with 1N HCl (2×50 mL), and the acid layers are extracted with dichloromethane (1×100 mL). The combined organics are dried (brine, MgSO 4 ), and concentrated in vacuo to afford a solid. The solid is purified by flash column chromatography (silica gel, CHCl 3 -MeOH) to afford the pure tris-silyl protected ester. 
     The above-prepared ester is dissolved in THF (8 mL) and TBAF is added as a THF solution (1M, 6 mL, 6 mmol) and the resultant solution is stirred for two hours at room temperature. The mixture is poured into half-saturated aqueous sodium chloride and extracted with dichloromethane (2×100 mL). The combined organics are washed (1×1N HCl, 1× water), dried (brine, MgSO 4 ), and concentrated in vacuo to obtain the crude gallic ester, which is purified by flash column chromatography (silica gel, CHCl 3 -MeOH) to afford the pure desired material. 
     Example 6 
     Phosphonoacetic Acid Ester of Compound 5 
     
       
                 
         
             
             
         
      
     
     A mixture of phosphonoacetic acid (2 mmol, 280 mg), compound 5 (776 mg, 2 mmol) and 4-dimethylaminopyridine (2.5 eq, 305 mg) in dichloromethane (15 mL) is stirred while EDC-HCl (384 mg, 2.0 mmol) is added. The resultant mixture is stirred for eight hours at room temperature. The mixture is poured into 1N HCl (100 mL) and is extracted with dichloromethane (2×100 mL). The organic layers are combined, dried (brine, MgSO 4 ) and concentrated. The residue is purified by reversed-phase HPLC to afford the desired phosphonoacetic acid ester of compound 5.