Pharmaceutical compositions and treatment methods-6

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 pharmaceutical formulation comprising one or more excipients and 3α,16α,17β-trihydroxy-5α-androstane, 3α,16α-dihydroxy-17-oxo-5α-androstane, 3β,16β,17β-trihydroxy-5α-androstane, 3β,16α-dihydroxy-17-oxo-5α-androstane, 3α,16β,17β-trihydroxy-5α-androstane, 3α,16β-dihydroxy-17-oxo-5α-androstane, 3β,16β-dihydroxy-17-oxo-5α-androstane, 3α,16α,17β-trihydroxy-5β-androstane, 3α,16α-dihydroxy-17-oxo-5β-androstane, 3β,16α,17β-trihydroxy-5β-androstane, 3β,16α-dihydroxy-17-oxo-5β-androstane, 3α,16β,17β-trihydroxy-5β-androstane, 3α,16β-dihydroxy-17-oxo-5β-androstane, 3β,16β-dihydroxy-17-oxo-5β-androstane or a 2-oxa, 11-oxa or 19-nor analog of any of these compounds.  
     
     
         2 . The pharmaceutical formulation of  claim 1  wherein the compound is 3α,16α,17β-trihydroxy-5α-androstane.  
     
     
         3 . The pharmaceutical formulation of  claim 1  wherein the compound is 3α,16α-dihydroxy-17-oxo-5α-androstane.  
     
     
         4 . A pharmaceutical formulation for buccal or sublingual administration comprising one or more excipients and a compound wherein the compound is 16α-fluoro-17-oxoandrost-5-ene, 3α-hydroxy-16α-fluoro-17-oxoandrost-5-ene, 3β-hydroxy-16α-fluoro-17-oxoandrost-5-ene 7α-hydroxy-16α-fluoro-17-oxoandrost-5-ene, 7β-hydroxy-16α-fluoro-17-oxoandrost-5-ene, 16α-fluoro-7,17-dioxoandrost-5-ene.  
     
     
         5 . The pharmaceutical formulation of  claim 4  wherein the compound is micronized.  
     
     
         6 . The pharmaceutical formulation of  claim 4  wherein the compound is 16α-fluoro-17-oxoandrost-5-ene.  
     
     
         7 . A pharmaceutical formulation comprising one or more excipients and two or more of 3β-hydroxy-16α-bromo-17-oxo-5α-androstane, 3β-hydroxy-16β-bromo-17-oxo-5α-androstane and 3β-hydroxy-16α-bromo-17-oxo-5α-androstane hemihydrate.  
     
     
         8 . The pharmaceutical formulation of  claim 7  wherein the pharmaceutical formulation is for oral, buccal, sublingual or aerosol administration.  
     
     
         9 . The pharmaceutical formulation of  claim 7  comprising 7 3β-hydroxy-16β-bromo-17-oxo-5α-androstane and 3β-hydroxy-16α-bromo-17-oxo-5α-androstane hemihydrate.  
     
     
         10 . The pharmaceutical formulation of  claim 9  wherein the pharmaceutical formulation is for oral, buccal, sublingual or aerosol administration.  
     
     
         11 . A method to increase the numbers or activity of neutrophils, dendritic cells, macrophages or monocytes in a human or a primate having or subject to developing an innate immune suppression condition or a symptom thereof comprising administering an effective amount of a compound having the formula  
       
         
           
           
               
               
           
         
       
       wherein the dotted lines are optional double bonds and when hydrogen is present at the 5-position, it is in the α-configuration; 
 R 1  is —OR PR , —SR PR , —N(R PR ) 2 , —O—Si—(R 13 ) 3 , an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a sulfite ester, a sulfate ester, an amino acid, a peptide, an ether, a thioether, a carbonate, a carbamate, an optionally substituted monosaccharide or an optionally substituted oligosaccharide;  
 R 2  and R 3  independently are —H, —OR PR , —SR PR , —N(R PR ) 2 , —O—Si—(R 13 ) 3 , —CN, ═O, ═S, ═NOH, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a sulfite ester, a sulfate ester, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, a halogen, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide or an optionally substituted oligosaccharide;  
 R 4  independently are —H, —OR PR , —SR PR , —N(R PR ) 2 , —O—Si—(R 13 ) 3 , —CN, ═O, ═S, ═NOH, 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, a carbonate, a carbamate, a thioacetal, an alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide or an optionally substituted oligosaccharide, provided that both R 4  are not —H;  
 R 5  and R 6  independently are —H, an acyl group, a thioacyl group, a halogen, an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group;  
 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 —, where R 10  independently are —H, —OR PR , —SR PR , —N(R PR ) 2 , —O—Si—(R 13 ) 3 , —CN, ═O, ═S, ═NOH, ═CH 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 group, a thioacyl group, a carbonate, a carbamate, a thioacetal, a halogen, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, optionally substituted monosaccharide or optionally substituted oligosaccharide;  
 R 8  and R 9  independently are —CHR 10 —, —CHR 10 —CHR 10 —, —O—, —O—CHR 10 —, —S—, —S—CHR 10 —, —NR PR — or —NR PR —CHR 10 —, or R 8  or R 9  independently is absent, leaving a 5-membered ring-, where R 10  independently are —H, —N(R PR ) 2 , —CN, ═NOH, ═CH 2 , an amide, an acyl group, a thioacyl group, a halogen, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety or an optionally substituted heteroaryl moiety;  
 R 13  independently are C 1-6  alkyl; and  
 R PR  independently are —H or a protecting group.  
 
     
     
         12 . The method of  claim 11  wherein about 4 to about 40 mg/kg/day, of the compound is administered to the human or the primate.  
     
     
         13 . The method of  claim 12  wherein the compound is intermittently administered to the subject.  
     
     
         14 . The method of  claim 11  wherein the compound has the formula  
       
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 14  wherein 
 (1) R 1  and R 4  are —OH, R 2  and R 3  are —H, R 5  and R 6  are —CH 3  and R 7 , R 8  and R 9  are —CH 2 —; or  
 (2) R 1  and R 4  are —OH, R 2  is —H, R 3  is —F, —Cl, —Br or —I, R 5  and R 6  are —CH 3  and R 7 , R 8  and R 9  are —CH 2 —; or  
 (3) R 1 , R 2  and R 4  are —OH, R 3  is —H, R 5  and R 6  are —CH 3  and R 7 , R 8  and R 9  are —CH 2 —; or  
 (4) R 1 , R 2  and R 4  are —OH, R 3  is —F, —Cl, —Br or —I R 5  and R 6  are —CH 3  and R 7 , R 8  and R 9  are —CH 2 —; or  
 (5) R 1  is —OH, R 2  is —H, R 3  is —OH, —F or —Br, R 4  is ═O, R 5  and R 6  are —CH 3  and R 7 , R 8  and R 9  are —CH 2 —; or  
 (6) R 1  and R 2  are —OH, R 3  is —H, —F, —Cl or —Br, R 4  is ═O, R 5  and R 6  are —CH 3  and R 7 , R 8  and R 9  are —CH 2 —; or  
 (7) R 1 , R 3  and R 4  are —OH, R 2  is —H, R 5  and R 6  are —CH 3  and R 7 , R 8  and R 9  are —CH 2 —; or  
 (8) R 1 , R 2 , R 3  and R 4  are —OH, R 5  and R 6  are —CH 3  and R 7 , R 8  and R 9  are —CH 2 —; or  
 (9) R 1  and R 4  independently are —OR PR , —SR PR , —N(R PR ) 2 , an ester, a thioester, a monosaccharide, an oligosaccharide, a carbonate or a carbamate, R 2  and R 3  are —H, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (10) R 1  and R 4  independently are —OR PR , —SR PR , —N(R PR ) 2 , an ester, a thioester, a monosaccharide, an oligosaccharide, a carbonate or a carbamate, R 2  is —H, R 3  is —Br, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (11) R 1  and R 4  independently are —OR PR , —SR PR , —N(R PR ) 2 , an ester, a thioester, a monosaccharide, an oligosaccharide, a carbonate or a carbamate, R 2  is —H, R 3  is —F, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (12) R 1  and R 4  independently are —OR PR , —SR PR , —N(R PR ) 2 , an ester, a thioester, a monosaccharide, an oligosaccharide, a carbonate or a carbamate, R 2  is —H, R 3  is —OH, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (13) R 1  and R 4  independently are —OR PR , —SR PR , —N(R PR ) 2 , an ester, a thioester, a monosaccharide, an oligosaccharide, a carbonate or a carbamate, R 2  and R 3  are —OH, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (14) R 1  and R 4  independently are —OR PR , —SR PR , —N(R PR ) 2 , an ester, a thioester, a monosaccharide, an oligosaccharide, a carbonate or a carbamate, R 2  is —OH, R 3  is —H, —F, —Cl or —Br, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (15) R 1  is —H, R 2  is —OH or ═O, R 3  is —OH, —F, —Cl or —Br, R 4  is —OR PR , SR PR , —N(R PR ) 2 , an ester, a thioester, a monosaccharide, an oligosaccharide, a carbonate or a carbamate, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (16) R 1  and R 2  are —H, R 3  is —OH or ═O, —F, —Cl or —Br, R 4  is —OR PR , —SR PR , —N(R PR ) 2 , an ester, a thioester, a monosaccharide, an oligosaccharide, a carbonate or a carbamate, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (17) any of (1) through (16) above wherein R 9  is —O— or —NH— instead of —CH 2 — or —CH═; or  
 (18) any of (1) through (17) above wherein R 8  is —O— or —NH— instead of —CH 2 —; or  
 (19) any of (1) through (18) above wherein R 7  is —O—, —NH— or —CHR 10 —CH 2 -instead of —CH 2 —.  
 
     
     
         16 . The method of  claim 15  wherein about 4 to about 40 mg/kg/day, of the compound is administered to the human or the primate.  
     
     
         17 . The method of  claim 16  wherein the compound is intermittently administered to the subject.  
     
     
         18 . The method of  claim 17  wherein the compound has the formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 4  are —OH, R 2  and R 3  are —H and R 5  and R 6  are —CH 3 .  
     
     
         19 . A method to treat a condition selected from the group consisting of inflammation, osteoporosis, a bone fracture, a wound or trauma and a burn in a human or a primate having, or subject to developing the condition, wherein the compound has the structure  
       
         
           
           
               
               
           
         
       
       wherein, 
 R 1 , R 2 , R 3 , R 4 , R 5  and R 10  independently are —H, —OR PR , —SR PR , —N(R PR ) 2 , —N 3 , —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 group, a thioacyl group, a carbonate, a carbamate, a thioacetal, a halogen, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, or,  
 one more of R 2 , R 3  and R 10  independently are ═O, ═S, ═NOH or ═CH 2 , or,  
 R 4  is ═O, ═S or ═NOH, or,  
 R 3  and both R 4  together comprise a structure having the formula  
                     
 R 6  is —H;  
 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 —;  
 R 8  and R 9  independently are —CHR 10 —, —CHR 10 —CHR 10 —, —O—, —O—CHR 10 —, —S—, —S—CHR 10 —, —NR PR — or —NR PR —CHR 10 —, or R 8  or R 9  independently is absent, leaving a 5-membered ring;  
 R 13  independently is C 1-6  alkyl;  
 R PR  independently are —H or a protecting group;  
 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 where 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 group, a thioacyl group, a carbonate, a carbamate, a thioacetal, a halogen, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, or,  
 one more of the ring carbons are substituted with ═O, ═S, ═NOH, ═NOC(O)CH 3  or ═CH 2 ,  
 or D comprises two 5- or 6-membered rings, wherein the rings are fused or are linked by 1 or 2 bonds.  
 
     
     
         20 . The method of  claim 19  wherein the compound has the structure  
       
         
           
           
               
               
           
         
       
     
     
         21 . The method of  claim 20  wherein 
 (1) R 1  and R 4  are —OH, R 2  and R 3  are —H, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (2) R 1  and R 4  are —OH, R 2  is —H, R 3  is —Br, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (3) R 1  and R 4  are —OH, R 2  is —H, R 3  is —F, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (4) R 1 , R 2  and R 4  are —OH, R 3  is —H, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (5) R 1 , R 2  and R 4  are —OH, R 3  is —Br, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (6) R 1 , R 2  and R 4  are —OH, R 3  is —F, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (7) R 1 , R 3  and R 4  are —OH, R 2  is —H, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (8) R 1 , R 2 , R 3  and R 4  are —OH, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —;  
 (9) R 1  and R 4  independently are —OR PR , —SR PR , —N(R PR ) 2 , an ester, a thioester, a monosaccharide, an oligosaccharide, a carbonate or a carbamate, R 2  and R 3  are —H, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (10) R 1  and R 4  independently are —OR PR , —SR PR , —N(R PR ) 2 , an ester, a thioester, a monosaccharide, an oligosaccharide, a carbonate or a carbamate, R 2  is —H, R 3  is —Br, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (11) R 1  and R 4  independently are —OR PR , —SR PR , —N(R PR ) 2 , an ester, a thioester, a monosaccharide, an oligosaccharide, a carbonate or a carbamate, R 2  is —H, R 3  is —F, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (12) R 1  and R 4  independently are —OR PR , —SR PR , —N(R PR ) 2 , an ester, a thioester, a monosaccharide, an oligosaccharide, a carbonate or a carbamate, R 2  is —H, R 3  is —OH, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (13) R 1  and R 4  independently are —OR PR , —SR PR , —N(R PR ) 2 , an ester, a thioester, a monosaccharide, an oligosaccharide, a carbonate or a carbamate, R 2  and R 3  are —OH, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (14) R 1  and R 4  independently are —OR PR , —SR PR , —N(R PR ) 2 , an ester, a thioester, a monosaccharide, an oligosaccharide, a carbonate or a carbamate, R 2  is —OH, R 3  is —H, —F, —Cl or —Br, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (15) R 1  is —H, R 2  is —OH or ═O, R 3  is —OH, —F, —Cl or —Br, R 4  is —OR PR , —SR PR , —N(R PR ) 2 , an ester, a thioester, a monosaccharide, an oligosaccharide, a carbonate or a carbamate, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (16) R 1  and R 2  are —H, R 3  is —OH or ═O, —F, —Cl or —Br, R 4  is —OR PR , —SR PR , —N(R PR ) 2 , an ester, a thioester, a monosaccharide, an oligosaccharide, a carbonate or a carbamate, R 5  is —CH 3 , R 7 , R 8  and R 9  are —CH 2 —; or  
 (17) any of (1) through (16) above wherein R 9  is —O— or —NH— instead of —CH 2 — or —CH═; or  
 (18) any of (1) through (17) above wherein R 8  is —O— or —NH— instead of —CH 2 —; or  
 (19) any of (1) through (18) above wherein R 7  is —O—, —NH— or —CHR 10 —CH 2 -instead of —CH 2 —.  
 
     
     
         22 . The method of  claim 20  wherein the condition is osteoporosis or a bone fracture and the compound is 3α,17β-dihydroxy-19-norandrost-4-ene or 3α,17β-dihydroxy-19-norandrost-5-ene.