Neurological disorder treatment methods

Abstract

The invention provides compositions comprising formula 1 steroids, e.g., 16α-bromo-3β-hydroxy-5α-androstan-17-one hemihydrate and one or more excipients, typically wherein the composition comprises less than about 3% water. The compositions are useful to make improved pharmaceutical formulations. The invention also provides methods of intermittent dosing of steroid compounds such as analogs of 16α-bromo-3β-hydroxy-5α-androstan-17-one and compositions useful in such dosing regimens. The invention further provides compositions and methods to inhibit pathogen (viral) replication, ameliorate symptoms associated with immune dysregulation and to modulate immune responses in a subject using certain steroids and steroid analogs. The invention also provides methods to make and use these immunomodulatory compositions and formulations.

1 . A method to treat a subject having, or subject to developing, a neurological disorder comprising administering to the subject an effective amount of 
 (i) 16α-bromoepiandrosterone hemihydrate, or    (ii) 16α-bromoepiandrosterone, 16β-bromoepiandrosterone, 16α-iodoepiandrosterone, 16β-iodoepiandrosterone, 3β,16α,17β-trihydroxyandrostane, 3β,16α,17β-trihydroxyandrostane, 3β,16α-dihydroxy-17-oxoandrostane, 3α,16α-dihydroxy-17-oxoandrostane, 3β,16β-dihydroxy-17-oxoandrostane, 3β,17β-dihydroxy-16α-flurorandrost-5-ene, 3β,17β-dihydroxyandrost-5-ene, 3α,17β-dihydroxyandrost-5-ene, 3β,17β-dimercaptoandrost-5-ene, 3α,17β-dimercaptoandrost-5-ene, 3β-mercapto-17β-hydroxyandrost-5-ene, 3α-mercapto-17β-hydroxyandrost-5-ene, 3β,17β-dihydroxyandrost-1,5-diene, 3α,17β-dihydroxyandrost-1,5-diene, 3β,16α,17β-trihydroxyandrost-1,5-diene, 3α,16α,17β-trihydroxyandrost-1,5-diene, 3β,7β,17β-trihydroxyandrost-5-ene, 3β-mercapto-7β,17β-dihydroxyandrost-5-ene, 3α,7β,17β-trihydroxyandrost-5-ene, 3β,16α,17β-trihydroxyandrost-5-ene, 3β,17β-dihydroxy-16α-flurorandrost-1,5-diene, 3β,7β,17β-trihydroxyandrost-1,5-diene, 3β-mercapto-7β,17β-dihydroxyandrost-1,5-diene or 3β,16α,17β-trihydroxyandrost-1,5-diene or a 2-oxa, 2-thia, 2-aza or 19-nor analog of any of these compounds or an ester, ether, carbonate, carbamate, thioacetal, thioester or thioether analog of any of these compounds, wherein the ester, ether, thioacetal, thioester or thioether is a C1-C50 moiety that is optionally substituted with 1, 2 or 3 independently selected —O—, —S—, —NH—, —C(O)—, ═O, ═S, —NH 2 , —C(O)OH, —O—C(O)—H, —OH, —SH, —NO 2 , —CN, —NHC(O)—, —C(O)NH—, —OC(O)—, —C(O)O—, —O-A8, —S-A8, —C(O)-A8, —OC(O)-A8, —C(O)O-A8, ═N—, —N═, ═N—OH, or halogen moieties or atoms where A8 is C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 1-4  alkyl-aryl, aryl or C 0-4  alkyl-C 2-9  heterocycle, or    (iii) a compound having the structure                                            wherein the dotted lines are optional double bonds and X is O or S;    R 1  is —H, —OH, —OR PR , —SH, —SR PR , —N 3 , —N(R PR ) 2 , —O—Si—(R 13 ) 3 , —CN, —NO 2 , —C(O)—CH 3 , —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl, a thioacyl, a carbonate, a carbamate, a thioacetal, optionally substituted heteroaryl, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer;    R 2  is —OH, —OR PR , ═O, —SH, —SR PR , ═S, ═CH 2 , —N 3 , —CN, —NO 2 , ═NOH, ═NOC(O)CH 3 , an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl, a thioacyl, a carbonate, a carbamate, a thioacetal, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl moiety, optionally substituted heteroaryl, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer;    R 3  is —OH, OR PR , ═O, —SH, SR PR , ═S, ═CH 2 , —N 3 , —O—Si—(R 13 ) 3 , —CN, —NO 2 , ═NOH, ═NOC(O)CH 3 , —C(O)—CH 3 , —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl, a thioacyl, a carbonate, a carbamate, a thioacetal, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl moiety, optionally substituted heteroaryl, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer;    R 4  is —SH, —SR PR , ═S, —N(R PR ) 2 , a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, a thioether, a thioacyl, a carbonate, a carbamate, a thioacetal, optionally substituted heteroaryl, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer;    R 5  and R 6  independently are —H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;    R 7  is —CHR 10 —, —CHR 10 —CHR 10 —, —CHR 10 —CHR 10 —CHR 10 —, —CHR 10 —O—CHR 10 —, —CHR 10 —S—CHR 10 —, —CHR 10 —NR PR —CHR 10 —, —O—, —O—CHR 10 —, —S—, —S—CHR 10 —, —NR PR — or —NR PR —CHR 10 —, wherein R 10  independently are —H, —OH, —OR PR , ═O, —SH, —SR PR , ═S, ═CH 2 , —N 3 , —NH 2 , —N(R PR ) 2 , —O—Si—(R 13 ) 3 , —CN, —NO 2 , ═NOH, ═NOC(O)CH 3 , —C(O)—CH 3 , —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl, a thioacyl, a carbonate, a carbamate, a thioacetal, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl moiety, optionally substituted heteroaryl, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer;    R 8  is —CHR 10 —, —CHR 10 —CHR 10 —, —O—, —O—CHR 10 —, —S—, —S—CHR 10 —, —NR PR — or —NR PR —CHR 10 —, or R 8  is absent, leaving a 5-membered ring, wherein R 10  independently are —H, —OH, —OR PR , ═O, —SH, —SR PR , ═S, ═CH 2 , —N 3 , —NH 2 , —N(R PR ) 2 , —O—Si—(R 13 ) 3 , —CN, —NO 2 , ═NOH, ═NOC(O)CH 3 , —C(O)—CH 3 , —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl, a thioacyl, a carbonate, a carbamate, a thioacetal, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl moiety, optionally substituted heteroaryl, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer;    R 9  is —CHR 10 —, —CHR 10 —CHR 10 —, —O—, —O—CHR 10 —, —S—, —S—CHR 10 —, —NR PR — or —NR PR —CHR 10 —, or R 9  is absent, leaving a 5-membered ring, wherein R 10  independently are —H, —SH, —SR PR , ═S, ═CH 2 , —N 3 , —NH 2 , —N(R PR ) 2 , —O—Si—(R 13 ) 3 , —CN, —NO 2 , ═NOH, ═NOC(O)CH 3 , —C(O)—CH 3 , —F, —Cl, —Br, —I, a thioester, an amide, an amino acid, a peptide, a thioether, an acyl, a thioacyl, a carbonate, a carbamate, a thioacetal, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl moiety, optionally substituted heteroaryl, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer;    D is a heterocycle or a 4-, 5-, 6- or 7-membered ring that comprises saturated carbon atoms, wherein 1, 2 or 3 ring carbon atoms of the 4-, 5-, 6- or 7-membered ring are optionally independently substituted with —O—, —S— or —NR PR — or where 1, 2 or 3 hydrogen atoms of the heterocycle or 1 or 2 hydrogen atoms of the 4-, 5-, 6- or 7-membered ring are substituted with —OR PR , —SR PR , —N(R PR ) 2 , —O—Si—(R 3 ) 3 , —CN, —NO 2 , an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl, a thioacyl, a carbonate, a carbamate, a thioacetal, a halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl moiety, optionally substituted heteroaryl, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer, or, one more of the ring carbons are substituted with ═O or ═S, or D comprises two 5- or 6-membered rings, wherein the rings are fused or are linked by 1 or 2 bonds;    R PR  independently or together are —H or a protecting group; and    R 13  independently are C 1 -C 6  alkyl.    
     
     
         2 . The method of  claim 1  wherein R 1 , R 2  and R 4  independently are —OH, ═O—SH, ═S, an ester, an ether, a thioester or a thioether, R 3  is —H, —OH, ═O, —SH, ═S or —F and R 5  is —CH 3  or —CH 2 OH and R 6  is —H or —CH 3 .  
     
     
         3 . The method of  claim 2  wherein R 7  and R 8  are —CH 2 —, R 9  is —O—, —S—, —CH 2 — or —CH═ and a double bond is present at the 5-6 position and optionally at the 1-2 position.  
     
     
         4 . The method of  claim 3  wherein the neurological disorder is Alzheimer's Disease, Parkinson's Disease, schizophrenia or multiple sclerosis.  
     
     
         5 . The method of  claim 4  wherein the compound is 16α-bromoepiandrosterone, 16β-bromoepiandrosterone, 16α-iodoepiandrosterone, 16β-iodoepiandrosterone, 3β,16α,17β-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane, 3β,16α-dihydroxy-17-oxoandrostane, 3α,16α-dihydroxy-17-oxoandrostane, 3β,16β-dihydroxy-17-oxoandrostane, 3β,17β-dihydroxy-16α-flurorandrost-5-ene, 3β,17β-dihydroxyandrost-5-ene, 3α,17β-dihydroxyandrost-5-ene, 3β,17β-dimercaptoandrost-5-ene, 3α,17β-dimercaptoandrost-5-ene, 3β-mercapto-17β-hydroxyandrost-5-ene, 3α-mercapto-17β-hydroxyandrost-5-ene, 3β,17β-dihydroxyandrost-1,5-diene, 3α,17β-dihydroxyandrost-1,5-diene, 3β,16α,17β-trihydroxyandrost-1,5-diene, 3α,16α,17β-trihydroxyandrost-1,5-diene, 3β,7β,17β-trihydroxyandrost-5-ene, 3α,7β,17β-trihydroxyandrost-5-ene, 3β,16α,17β-trihydroxyandrost-5-ene, 3β,17β-dihydroxy-16α-flurorandrost-1,5-diene, 3β,7β,17β-trihydroxyandrost-1,5-diene or 3β,16α,17β-trihydroxyandrost-1,5-diene or a 2-oxa, 2-thia, 2-aza or 19-nor analog of any of these compounds or an ester, ether, carbonate, carbamate, thioacetal, thioester or thioether analog of any of these compounds, wherein the ester, ether, thioacetal, thioester or thioether is a C1-C50 moiety that is optionally substituted with 1, 2 or 3 independently selected —O—, —S—, —NH—, —C(O)—, ═O, ═S, —NH 2 , —C(O)OH, —O—C(O)—H, —OH, —SH, —NO 2 , —CN, —NHC(O)—, —C(O)NH—, —OC(O)—, —C(O)O—, —O-A8, —S-A8, —C(O)-A8, —OC(O)-A8, —C(O)O-A8, ═N—, —N═, ═N—OH, or halogen moieties or atoms where A8 is C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 1-4  alkyl-aryl, aryl or C 0-4  alkyl-C 2-9  heterocycle.  
     
     
         6 . The method of  claim 4  wherein the compound is 16α-bromoepiandrosterone hemihydrate.  
     
     
         7 . A method to inhibit angiogenesis in a subject having a cancer or precancer, comprising administering to the subject an effective amount of 
 (i) 16α-hydroxyepiandrosterone, 3β,16α-dihydroxy-17-oxoandrostane, 3α,16α-dihydroxy-17-oxoandrostane, 3β,16α,17β-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane, 3β,16α,17α-trihydroxyandrostane, 16β-bromoepiandrosterone, 16β-iodoepiandrosterone, 3β,17β-dimercaptoandrost-5-ene, 3α,17β-dimercaptoandrost-5-ene, 3β-mercapto-17β-hydroxyandrost-5-ene, 3α-mercapto-17β-hydroxyandrost-5-ene, 3β-mercapto-7β,17β-dihydroxyandrost-5-ene, 3α-mercapto-7β,17β-dihydroxyandrost-5-ene, 3β-hydroxy-7,17-dioxoandrost-5-ene, 3β-acetoxy-7,17-dioxoandrost-5-ene, 3β-propionoxy-7,17-dioxoandrost-5-ene, 3α,7α-dihydroxy-17-oxoandrost-5-ene, 3β,7β-dihydroxy-17-oxoandrost-5-ene, 3β-acetoxy-7α-hydroxy-17-oxoandrost-5-ene, 3β-acetoxy-7β-hydroxy-17-oxoandrost-5-ene, 3β-propionoxy-7α-hydroxy-17-oxoandrost-5-ene, 3β-propionoxy-7β-hydroxy-17-oxoandrost-5-ene or a 2-oxa, 2-aza or 2-thia analog of any of these compounds, or    (ii) 16α-bromoepiandrosterone hemihydrate, or    (iii) 16α-bromoepiandrosterone, 16α-iodoepiandrosterone, 16α-fluoroepiandrosterone, 16α-chloroepiandrosterone, 16β-bromoepiandrosterone, 16β-iodoepiandrosterone, 16β-fluoroepiandrosterone, 16β-chloroepiandrosterone, 3β,16α-dihydroxy-17-oxoandrostane, 3α,16α-dihydroxy-17-oxoandrostane, 3β,16α,17β-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane, 3β-hydroxy-16α-bromo-17-oxo-5β-androstane, 3β-hydroxy-16α-iodo-17-oxo-5β-androstane, 3β-hydroxy-16α-fluoro-17-oxo-5β-androstane, 3β-hydroxy-16α-chloro-17-oxo-5β-androstane, 3β-hydroxy-16β-bromo-17-oxo-5β-androstane, 3β-hydroxy-16β-iodo-17-oxo-5β-androstane, 3β-hydroxy-16β-fluoro-17-oxo-5β-androstane, 3β-hydroxy-16β-chloro-17-oxo-5β-androstane, 3β,16α,17β-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane, 3β,16α-dihydroxy-17-oxoandrostane, 3α,16α-dihydroxy-17-oxoandrostane, 3β,16β-dihydroxy-17-oxoandrostane, 3β,17β-dihydroxy-16α-flurorandrost-5-ene, 3α,17β-dihydroxyandrost-5-ene, 3β,17β-dihydroxy-7-oxoandrost-5-ene, 3α,17β-dihydroxy-7-oxoandrost-5-ene, 3β-hydroxy-7,17-dioxoandrost-5-ene, 3α-hydroxy-7,17-dioxoandrost-5-ene, 3β,17β-dihydroxyandrost-1,5-diene, 3α,17β-dihydroxyandrost-1,5-diene, 3β,16α,17β-trihydroxyandrost-1,5-diene, 3α,16α,17β-trihydroxyandrost-1,5-diene, 3β,7β,17β-trihydroxyandrost-5-ene, 3β,7β,17α-trihydroxyandrost-5-ene, 3α,7β,17β-trihydroxyandrost-5-ene, 3β,16α,17β-trihydroxyandrost-5-ene, 3β,17β-dihydroxy-16α-flurorandrost-1,5-diene, 3β,7β,17β-trihydroxyandrost-1,5-diene or 3β,16α,17β-trihydroxyandrost-1,5-diene or a 19-nor analog of any of these compounds or an ester, ether, thioacetal, thioester or thioether analog of any of these compounds, wherein the ester, ether, thioacetal, thioester or thioether is a C1-C50 moiety that is optionally substituted with 1, 2 or 3 independently selected —O—, —S—, —NH—, —C(O)—, ═O, ═S, —NH 2 , —C(O)OH, —O—C(O)—H, —OH, —SH, —NO 2 , —CN, —NHC(O)—, —C(O)NH—, —OC(O)—, —C(O)O—, —O-A8, —S-A8, —C(O)-A8, —OC(O)-A8, —C(O)O-A8, ═N—, —N═, ═N—OH, or halogen moieties or atoms where A8 is C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 1-4  alkyl-aryl, aryl or C 0-4  alkyl-C 2-9  heterocycle, or    (iv) a compound having the structure                          wherein the dotted lines are optional double bonds and X is O or S;    R 1  is —OH, —OR PR , —SH, —SR PR , —N 3 , —N(R PR ) 2 , —O—Si—(R 13 ) 3 , —CN, —NO 2 , —C(O)—CH 3 , —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl, a thioacyl, a carbonate, a carbamate, a thioacetal, optionally substituted heteroaryl, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer;    R 2  is —OH, OR PR , ═O, —SH, SR PR , ═S, —N(R PR ) 2 , —N 3 , —CN, —NO 2 , ═NOH, ═NOC(O)CH 3 , an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl, a thioacyl, a carbonate, a carbamate, a thioacetal, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl moiety, optionally substituted heteroaryl, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer;    R 3  is —OH, OR PR , ═O, —SH, SR PR , ═S, —N 3 , —O—Si—(R 13 ) 3 , —CN, —NO 2 , ═NOH, ═NOC(O)CH 3 , —C(O)—CH 3 , —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl, a thioacyl, a carbonate, a carbamate, a thioacetal, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl moiety, optionally substituted heteroaryl, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer;    R 4  is —SH, —SR PR , ═S, —N(R PR ) 2 , ═NOH, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, a thioether, a carbonate, a carbamate, a thioacetal, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer;    R 5  and R 6  independently are —H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;    R 7  is —CHR 10 —, —CHR 10 —CHR 10 —, —CHR 10 —CHR 10 —CHR 10 —, —CHR 10 —O—CHR 10 —, —CHR 10 —S—CHR 10 —, —CHR 10  —NR PR —CHR 10 —, —O—, —O—CHR 10 —, —S—, —S—CHR 10 —, —NR PR — or —NR PR —CHR 10 —, wherein R 10  independently are —H, —OH, —OR PR , ═O, —SH, —SR PR , ═S, ═CH 2 , —N 3 , —NH 2 , —N(R PR ) 2 , —O—Si—(R 13 ) 3 , —CN, —NO 2 , ═NOH, ═NOC(O)CH 3 , —C(O)—CH 3 , —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl, a thioacyl, a carbonate, a carbamate, a thioacetal, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl moiety, optionally substituted heteroaryl, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer;    R 8  is —CHR 10 —, —CHR 10 —CHR 10 —, —O—, —O—CHR 10 —, —S—, —S—CHR 10 —, —NR PR — or —NR PR —CHR 10 —, or R 8  is absent, leaving a 5-membered ring, wherein R 10  independently are —H, —OH, —OR PR , ═O, —SH, —SR PR , ═S, ═CH 2 , —N 3 , —N(R PR ) 2 , —O—Si—(R 13 ) 3 , —CN, —NO 2 , ═NOH, ═NOC(O)CH 3 , —C(O)—CH 3 , —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl, a thioacyl, a carbonate, a carbamate, a thioacetal, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl moiety, optionally substituted heteroaryl, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer;    R 9  is —CHR 10 —, —CHR 10 —CHR 10 —, —O—, —O—CHR 10 —, —S—, —S—CHR 10 —, —NR PR — or —NR PR —CHR 10 —, or R 9  is absent, leaving a 5-membered ring, wherein R 10  independently are —H, —SH, —SR PR , ═S, ═CH 2 , —N 3 , —N(R PR ) 2 , —O—Si—(R 13 ) 3 , —CN, —NO 2 , ═NOH, ═NOC(O)CH 3 , —C(O)—CH 3 , —F, —Cl, —Br, —I, a thioester, an amide, an amino acid, a peptide, a thioether, an acyl, a thioacyl, a carbonate, a carbamate, a thioacetal, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl moiety, optionally substituted heteroaryl, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer;    D is a heterocycle or a 4-, 5-, 6- or 7-membered ring that comprises saturated carbon atoms, wherein 1, 2 or 3 ring carbon atoms of the 4-, 5-, 6- or 7-membered ring are optionally independently substituted with —O—, —S— or —NR PR — or where 1, 2 or 3 hydrogen atoms of the heterocycle or 1 or 2 hydrogen atoms of the 4-, 5-, 6- or 7-membered ring are substituted with —OR PR , SR PR , N(R PR ) 2 , —O—Si—(R 13 ) 3 , —CN, —NO 2 , an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl, a thioacyl, a carbonate, a carbamate, a thioacetal, a halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl moiety, optionally substituted heteroaryl, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer, or, one more of the ring carbons are substituted with ═O or ═S, or D comprises two 5- or 6-membered rings, wherein the rings are fused or are linked by 1 or 2 bonds;    R PR  independently or together are —H or a protecting group; and    R 13  independently are C1-C6 alkyl.    
     
     
         8 . The method of  claim 7  wherein R 1 , R 2  and R 4  independently are —OH, ═O, —SH, ═S, an ester, an ether, a thioester or a thioether and R 3  is —H, —Br or —Cl.  
     
     
         9 . The method of  claim 8  wherein R 5  is —CH 3  or —CH 2 OH, R 6  is —H, —CH 3  or —CH 2 OH and R 7  and R 8  are —CH 2 —.  
     
     
         10 . The method of  claim 9  wherein R 9  is —O—, —S—, —CH 2 — or —CH═ and a double bond is present at the 5-6 position and optionally at the 1-2 position.  
     
     
         11 . The method of  claim 10  wherein R 1  is —OH, —O—C 2 H 5 , —O—CH 2 CH 2 CH 3 , —O—CH 2 CH 2 CH 2 CH 3 , —O—CH(CH 3 )CHCH 3 , —O—C(CH 3 ) 3 , —O—(CH 2 ) 4 CH 3 , —O—C(O)—CH 3 , —O—C(O)—C 2 H 5 , —O—C(O)—CH 2 CH 2 CH 3 , —O—C(O)—CH 2 CH 2 CH 2 CH 3 , —O—C(O)—CH 2 OH, —O—C(O)—CH 2 CH 2 OH, —O—C(O)—CH 2 CH 2 CH 2 OH, —O—C(O)—CH 2 SH, —O—C(O)—CH 2 CH 2 SH or —O—C(O)—CH 2 CH 2 CH 2 SH, R 2  is —OH, ═O, —SH or ═S and the compound has the structure  
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 7  wherein the compound is 16α-bromoepiandrosterone hemihydrate, 16α-hydroxyepiandrosterone, 3α,16α-dihydroxy-17-oxoandrostane, 3β,16α,17β-trihydroxyandrostane or 3α,16α,17β-trihydroxyandrostane.