Therapeutic treatment methods 2

Abstract

The invention relates to the use of compounds to ameliorate or treat a condition such as a cystic fibrosis, neutropenia or other exemplified conditions. Exemplary compounds that can be used include 3β-hydroxy-17β-aminoandrost-5-ene, 3β-hydroxy-16α-fluoro-17β-aminoandrost-5-ene, 3α-hydroxy-16α-fluoro-17β-aminoandrost-5-ene, 3β-hydroxy-16β-fluoro-17β-aminoandrost-5-ene, 1α,3β-dihydroxy-4α-fluoroandrost-5-ene-17-one, 1α,3β,17β-trihydroxy-4α-fluoroandrost-5-ene, 1β,3β-dihydroxy-6α-bromoandrost-5-ene, 1α-fluoro-3β,12α-dihydroxyandrost-5-ene-17-one, 1α-fluoro-3β,4α-dihydroxyandrost-5-ene and 4α-fluoro-3β,6α,17β-trihydroxyandrostane.

1 . A method to prevent, treat, ameliorate or slow the progression of cystic fibrosis, sickle cell disease, autism, neutropenia or thrombocytpoenia in a subject, or to treat a symptom of the cystic fibrosis, sickle cell disease, autism, neutropenia or thrombocytopenia, comprising administering to a subject, or delivering to the subject's tissues, an effective amount of a formula 1 compound having the structure 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a metabolic precursor or a metabolite thereof, wherein  
         R 10  moieties at the 5 (if present), 8, 9 and 14 positions respectively are in the α,α,α,α, α,α,α,β, α,α,β,α, α,β,α,α, β,α,α,α, α,α,β,β, α,β,α,β, β,α,α,β, β,α,β,α, β,β,α,α, α,β,β,α, α,β,β,β, β,α,β,β, β,β,α,β, β,β,β,α or β,β,β,β configurations,  
         wherein R 10A , R 10B , R 10C , R 10D  and R 10E  respectively are in the α,α, α,β, β,α or β,β configurations,  
         wherein, each R 1 , R 2 , R 3 , R 4 , R 5 , R 1 , R 10 , R 10A , R 10B , R 10C , R 10D  and R 10E  independently are —H, —OH, —OR PR , —SR PR , —N(R PR ) 2 , —O—Si—(R 13 ) 3 , —CHO, —CHS, —CN, —SCN, —NO 2 , —NH 2 , —COOH, —OSO 3 H, —OPO 3 H, an ester, a thioester, a thionoester, 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 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 heterocycle, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide, a polymer, or,  
         one more of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 10 , R 10A , R 10B , R 10C , R 10D  and R 10E  are ═O, ═S, ═N—OH, ═CH 2 , ═CH—CH 3 , or an independently selected spiro ring and the hydrogen atom or the second variable group that is bonded to the same carbon atom is absent, or,  
         one or more of two adjacent R 1 -R 6 , R 10 , R 10A , R 10B , R 10C , R 10D  and R 10E  comprise an independently selected epoxide, acetal, a thioacetal, ketal or thioketal;  
         R 7  is —C(R 10 ) 2 —, —C(R 10 ) 2 —C(R 10 ) 2 —, —C(R 10 ) 2 —C(R 10 ) 2 —C(R 10 ) 2 —, —C(R 10 ) 2 —O—C(R 10 ) 2 —, —C(R 10 ) 2 —S—C(R 10 ) 2 —, —C(R 10 ) 2 —NR PR —C(R 10 ) 2 —, —O—, —O—C(R 10 ) 2 —, —S—, —S—C(R 10 ) 2 —, NR PR — or —NR PR —C(R 10 ) 2 —;  
         R 8  and R 9  independently are —C(R 10 ) 2 —, —C(R 10 ) 2 —C(R 10 ) 2 —, —O—, —O—C(R 10 ) 2 —, —S—, —S—C(R 10 ) 2 —, —NR PR — or —NR PR —C(R 10 ) 2 —, or one or both of R 8  or R 9  independently are absent, leaving a 5-membered ring;  
         R 13  independently is C 1-6  alkyl; and  
         R PR  independently is —H or a protecting group, provided that one R 4  is —NH 2 , an optionally substituted amine, —N(R PR ) 2 , ═NOH, ═NO-optionally substituted alkyl, an amide, a carbamate or an N-linked amino acid, or the condition is cystic fibrosis or a sickle cell disease.  
       
     
     
         2 . The method of  claim 1  wherein one each of R 1 , R 2 , R 3  and R 4  are —H, and, when no double bond links the second R 1 , R 2 , R 3  and R 4  to the ring to which it is bonded and no double bond is present at the 16-17 position, then the second R 1 , R 2 , R 3  and R 4  respectively are in the α,α,α,α, α,α,α,β, α,α,β,α, α,β,α,α, β,α,α,α, α,α,β,β, α,β,α,β, β,α,α,β, β,α,β,α, β,β,α,α, α,β,β,α, α,β,β,β, β,α,β,β, β,β,α,β, β,β,β,α or β,β,β,β configurations and the second R 1 , R 2 , R 3  and R 4  are optionally independently selected from —H, —F, —Cl, —Br, —I, —OH, —SH, —NH 2 , —COOH, —CH 3 , —C 2 H 5 , —C(CH 3 ) 3 , —OCH 3 , —OC 2 H 5 , —CF 3 , —CH 2 OH, —C(O)CH 3 , —C(O)CH 2 OH, —C(O)CH 2 F, —C(O)CH 2 Cl, —C(O)CH 2 Br, —C(O)CH 2 I, —C(O)CF 3 , —C 2 F 5 , ═O, ═CH 2 , ═CHCH 3 , amino acid, carbamate, carbonate, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 ether, optionally substituted C 1 -C20 ester, optionally substituted C1-C 20  thioether, optionally substituted C1-C20 thioester, optionally substituted monosaccharide, optionally substituted disaccharide, optionally substituted oligosaccharide.  
     
     
         3 . The method of  claim 2  wherein 
 (a) R 10A  is bonded to the ring to which it is attached by a single bond and a double bond is present at (i) the 1-2 position, or (ii) the 1-2 and 16-17 positions; or    (b) R 10B  is bonded to the ring to which it is attached by a single bond and a double bond is present at the 4-5 position; or    (c) R 10C  is bonded to the ring to which it is attached by a single bond and a double bond is present at the 5-6 position; or    (d) R 10A  and R 10B  are bonded to the rings to which they are attached by a single bond and a double bond is present at (i) the 1-2 and 4-5 positions, or (ii) the 1-2, 4-5 and 16-17 positions;    (e) R 10 A and R 10C  are bonded to the rings to which they are attached by a single bond and a double bond is present at (i) the 1-2 and 5-6 positions, or (ii) the 1-2, 5-6 and 16-17 positions; or    (f) no double bond is present.    
     
     
         4 . The method of  claim 1  wherein the compounds of structure 5, 6, 7, 8, 9, 10, 11 and 12 have the structure  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         provided that if a double bond is present at the 1-2, 4-5 or 5-6 positions, then R 10A , R 10B  or R 10C  respectively are bonded to the ring to which they are linked by a single bond.  
       
     
     
         5 . The method of  claim 4  wherein (1) R 5  and R 6  respectively are in the α,α, α,β, β,α or β,β configuration and R 5  and R 6  are optionally both —CH 3  or are optionally selected from —H, —CH 3  and —CH 2 OH or (2) R 5  and R 6  are both in the 1-configuration and R 5  and R 6  are optionally both —H, —CH 3  or —CH 2 OH.  
     
     
         6 . The method of  claim 5  wherein R 10  at the 5, 8, 9 and 14-positions respectively are 
 (1) —H, —H, —H, —H;    (2) —H, —H, halogen (—F, —Cl, —Br or —I), —H;    (3) —H, —H, —H, —OH;    (4) —H, —H, halogen (—F, —Cl, —Br or —I), —OH;    (5)-optionally substituted alkyl (e.g., —CH 3 , —CH 2 OH, —CH 2 O-ester, —C 2 H 5 ), —H, —H, —H;    (6)-optionally substituted alkyl (e.g., —CH 3 , —CH 2 OH, —CH 2 O-ester, —C 2 H 5 ), —H, halogen (—F, —Cl, —Br or —I), —H;    (7)-optionally substituted alkyl (e.g., —CH 3 , —CH 2 OH, —CH 2 O-ester, —C 2 H 5 ), —H, —H, —OH;    (8)-acyl (e.g., —C(O)—(CH 2 ) 0-2 —CH 3 ), —H, —H, —H;    (9) -ester (e.g., acetoxy or propionoxy), —H, —H, —H;    (10) -ether (e.g., —O—(CH 2 ) 0-2 —CH 3 ), —H, —H, —H;    (11) -ester (e.g., acetoxy, propionoxy, —O—C(O)—(CH 2 ) 1-6 —H), —H, halogen (e.g., —F, —Cl, —Br), —H;    (12) -ester (e.g., acetoxy or propionoxy), —H, —H, —OH;    (13) —H, —H, —H, -acyl (e.g., —C(O)—(CH 2 ) 0-2 —CH 3 );    (14) —H, —H, —H, -ester (e.g., acetoxy or propionoxy); or    (15) —H, —H, —H, -ether (e.g., —O—(CH 2 ) 0-2 —CH 3 , —OCH 3 , —OC 2 H 5 , —OCH 2 OH, —OCH 2 F, —OCH 2 Br, —OCH 2 COOH, —OCH 2 NH 2 , —OCH 2 CH 2 OH, —OCH 2 CH 2 F, —OCH 2 CH 2 Br, —OCH 2 CH 2 COOH or —OCH 2 CH 2 NH 2 ).    
     
     
         7 . The method of  claim 6  wherein R 7  is —CH 2 —, —CHOH—, —CH(αR 10 )—, —CH(ester)-, —CH(alkoxy)- or —CH(halogen)- where the hydroxyl, ester or alkoxy group or the halogen atom is present in the α-configuration and the alkoxy group is optionally selected from —OCH 3 , —OC 2 H 5  and —OC 3 H 7  and the halogen atom is —F, —Cl, —Br or —I.  
     
     
         8 . The method of  claim 6  wherein R 8  is —CH 2 —, —CF 2 —, —CHOH—, —CH(αR 10 )—, —CH(ester)-, —CH(alkoxy)- or —CH(halogen)- where the hydroxyl, ester or alkoxy group or the halogen atom is present in the α-configuration and the alkoxy group is optionally selected from —OCH 3 , —OC 2 H 5  and —OC 3 H 7  and the halogen atom is —F, —Cl, —Br or —I.  
     
     
         9 . The method of  claim 1  wherein the formula 1 compound is an analog of 16α-bromo-35-hydroxy-5α-androstan-17-one, 16α-fluoro-3β-hydroxy-5α-androstan-17-one, 16α-chloro-3β-hydroxy-5α-androstan-17-one, 16β-bromo-3β-hydroxy-5α-androstan-17-one, 16-fluoro-3β-hydroxy-5α-androstan-17-one, 16β-chloro-3β-hydroxy-5α-androstan-17-one, 16α,3β-dihydroxy-5α-androstan-17-one, 1β,3β-dihydroxy-5α-androstan-17-one, 1 6α,3α-dihydroxy-5α-androstan-17-one, 16β,3α-dihydroxy-5α-androstan-17-one, 16α-bromo-3β-hydroxy-5α-androstan-17-one hemihydrate, 3α-hydroxy-16α-fluoroandrostane-17-one, 3β-hydroxy-16α-fluoroandrostane-17-one, 17α-hydroxy-16α-fluoroandrostane-3-one, 17β-hydroxy-16α-fluoroandrostane-3-one, 17α-hydroxy-16α-fluoroandrostane-4-one, 17β-hydroxy-16α-fluoroandrostane-4-one, 17α-hydroxy-16α-fluoroandrostane-6-one, 17β-hydroxy-16α-fluoroandrostane-6-one, 17α-hydroxy-16α-fluoroandrostane-7-one, 17β-hydroxy-16α-fluoroandrostane-7-one, 17α-hydroxy-16α-fluoroandrostane-11-one, 17β-hydroxy-16α-fluoroandrostane-11-one, 16α-fluoroandrost-5-ene-17-one, 7α-hydroxy-16α-fluoroandrost-5-ene-17-one, 7β-hydroxy-16α-fluoroandrost-5-ene-17-one, 4α-hydroxy-16α-fluoroandrost-5-ene-17-one, 3α-hydroxy-16α-fluoroandrost-5-ene-17-one, 3β-hydroxy-16α-fluoroandrost-5-ene-17-one, 4β-hydroxy-16α-fluoroandrost-5-ene-17-one, 6α-hydroxy-16α-fluoroandrost-5-ene-17-one, 6β-hydroxy-16α-fluoroandrost-5-ene-17-one, 11α-hydroxy-16α-fluoroandrost-5-ene-17-one, 11β-hydroxy-16α-fluoroandrost-5-ene-17-one, 4α,17β-dihydroxy-16α-fluoroandrost-5-ene, 4β,17β-dihydroxy-16α-fluoroandrost-5-ene, 6α,17β-dihydroxy-16α-fluoroandrost-5-ene, 6β, 17β-dihydroxy-16α-fluoroandrost-5-ene, 11α,17β-dihydroxy-16α-fluoroandrost-5-ene, 11β,17β-dihydroxy-16α-fluoroandrost-5-ene, 4α,17α-dihydroxy-16α-fluoroandrost-5-ene, 4β,17α-dihydroxy-16α-fluoroandrost-5-ene, 6α,17α-dihydroxy-16α-fluoroandrost-5-ene, 6β,17α-dihydroxy-16α-fluoroandrost-5-ene, 11α,17α-dihydroxy-16α-fluoroandrost-5-ene, 11β,17α-dihydroxy-16α-fluoroandrost-5-ene, 7α,17β-dihydroxy-16α-fluoroandrost-5-ene, 7β,17β-dihydroxy-16α-fluoroandrost-5-ene, 3α,17β-dihydroxy-16α-fluoroandrost-5-ene, 3β,17β-dihydroxy-16α-fluoroandrost-5-ene, 3α,17α-dihydroxy-16α-fluoroandrost-5-ene, 3β,17α-dihydroxy-16α-fluoroandrost-5-ene, 1α,17β-dihydroxy-16α-fluoroandrost-5-ene, 1β,17β-dihydroxy-16α-fluoroandrost-5-ene, 2α,17β-dihydroxy-16α-fluoroandrost-5-ene, 2β,17β-dihydroxy-16α-fluoroandrost-5-ene, 12α,17β-dihydroxy-16α-fluoroandrost-5-ene, 12β,17β-dihydroxy-16α-fluoroandrost-5-ene, 1α,17α-dihydroxy-16α-fluoroandrost-5-ene, 1β,17α-dihydroxy-16α-fluoroandrost-5-ene, 2α,17α-dihydroxy-16α-fluoroandrost-5-ene, 2β,17α-dihydroxy-16α-fluoroandrost-5-ene, 12α,17α-dihydroxy-16α-fluoroandrost-5-ene, 12β,17α-dihydroxy-16α-fluoroandrost-5-ene, 15α,17β-dihydroxy-16α-fluoroandrost-5-ene, 15β,17β-dihydroxy-16α-fluoroandrost-5-ene, 17β,18-dihydroxy-16α-fluoroandrost-5-ene, 17β,19-dihydroxy-16α-fluoroandrost-5-ene, 15α,17α-dihydroxy-16α-fluoroandrost-5-ene, 15β,17α-dihydroxy-16α-fluoroandrost-5-ene, 17α,18-dihydroxy-16α-fluoroandrost-5-ene, 17α,19-dihydroxy-16α-fluoroandrost-5-ene, 16α-fluoroandrost-4-ene-17-one, 7α-hydroxy-16α-fluoroandrost-4-ene-17-one, 7β-hydroxy-16α-fluoroandrost-4-ene-17-one, 3α-hydroxy-16α-fluoroandrost-4-ene-17-one, 3β-hydroxy-16α-fluoroandrost-4-ene-17-one, 4α-hydroxy-16α-fluoroandrost-4-ene-17-one, 4β-hydroxy-16α-fluoroandrost-4-ene-17-one, 6α-hydroxy-16α-fluoroandrost-4-ene-17-one, 6β-hydroxy-16α-fluoroandrost-4-ene-17-one, 11α-hydroxy-16α-fluoroandrost-4-ene-17-one, 11β-hydroxy-16α-fluoroandrost-4-ene-17-one, 4α,17β-dihydroxy-16α-fluoroandrost-4-ene, 4β,17β-dihydroxy-16α-fluoroandrost-4-ene, 6α,17β-dihydroxy-16α-fluoroandrost-4-ene, 6β,17β-dihydroxy-16α-fluoroandrost-4-ene, 11α,17β-dihydroxy-16α-fluoroandrost-4-ene, 11β,17β-dihydroxy-16α-fluoroandrost-4-ene, 4α,17α-dihydroxy-16α-fluoroandrost-4-ene, 4β,17α-dihydroxy-16α-fluoroandrost-4-ene, 6α,17α-dihydroxy-16α-fluoroandrost-4-ene, 6β,17α-dihydroxy-16α-fluoroandrost-4-ene, 11α,17α-dihydroxy-16α-fluoroandrost-4-ene, 11β,17α-dihydroxy-16α-fluoroandrost-4-ene, 7α,17β-dihydroxy-16α-fluoroandrost-4-ene, 7β,17β-dihydroxy-16α-fluoroandrost-4-ene, 3α,17β-dihydroxy-16α-fluoroandrost-4-ene, 3β,17β-dihydroxy-16α-fluoroandrost-4-ene, 3α,17α-dihydroxy-16α-fluoroandrost-4-ene, 3β,17α-dihydroxy-16α-fluoroandrost-4-ene, 1α,17β-dihydroxy-16α-fluoroandrost-4-ene, 1β,17β-dihydroxy-16α-fluoroandrost-4-ene, 2α,17β-dihydroxy-16α-fluoroandrost-4-ene, 2β,17β-dihydroxy-16α-fluoroandrost-4-ene, 12α,17β-dihydroxy-16α-fluoroandrost-4-ene, 12β,17β-dihydroxy-16α-fluoroandrost-4-ene, 1α,17α-dihydroxy-16α-fluoroandrost-4-ene, 1β,17α-dihydroxy-16α-fluoroandrost-4-ene, 2α,17α-dihydroxy-16α-fluoroandrost-4-ene, 2β,17α-dihydroxy-16α-fluoroandrost-4-ene, 12α,17α-dihydroxy-16α-fluoroandrost-4-ene, 12β,17α-dihydroxy-16α-fluoroandrost-4-ene, 15α,17β-dihydroxy-16α-fluoroandrost-4-ene, 15β,17β-dihydroxy-16α-fluoroandrost-4-ene, 17β,18-dihydroxy-16α-fluoroandrost-4-ene, 17β,19-dihydroxy-16α-fluoroandrost-4-ene, 15α,17α-dihydroxy-16α-fluoroandrost-4-ene, 15β,17α-dihydroxy-16α-fluoroandrost-4-ene, 17α,18-dihydroxy-16α-fluoroandrost-4-ene, 1 7α, 19-dihydroxy-16α-fluoroandrost-4ene, 3β,17β-dihydroxyandrost-5-ene, 3β-hydroxy-7,17-dioxoandrost-5-ene, 3α-hydroxy-7,17-dioxoandrost-5-ene, 3,17-dioxoandrost-5-ene, 3,17-dioxoandrost-4-ene, 3,17-dioxoandrost-1,4-diene, 3β,7β,17β-trihydroxyandrost-5-ene, 3β,7β,17β-trihydroxyandrostane, 3β,16α-dihydroxy-17-oxoandrostane, 3α,16α-dihydroxy-17-oxoandrostane, 3β,16β-dihydroxy-17-oxoandrostane, 3α,16β-dihydroxy-17-oxoandrostane, 3β,16α,17β-trihydroxyandrostane, 3β,16β,17β-trihydroxyandrostane, 3β,16α,17α-trihydroxyandrostane, 3β,16β,17α-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane or 3α,16β,17β-trihydroxyandrostane that is within the scope of the  claim 1  compounds, optionally wherein —NH 2 , a substituted amine, a carbamate or an amide is present at R 4 , or an R 10  is a hydroxyl, thiol, optionally substituted alkyl or a halogen at the 1-, 2-, 4-, 6-, 7-, 9-11-, 12-, 14-, 15- or 16-position, wherein the R 10  is present in the α-configuration or the β-configuration.  
     
     
         10 . The method of  claim 1  wherein the subject has, or is subject or susceptible to developing, neutropenia.  
     
     
         11 . The method of  claim 10  wherein the subject is a human or another primate and wherein the neutropenia is postinfectious neutropenia, autoimmune neutropenia, chronic idiopathic neutropenia or a neutropenia resulting from or potentially resulting result from a cancer chemotherapy, chemotherapy for an autoimmune disease, an antiviral therapy, radiation exposure, tissue or solid organ allograft or xenograft rejection or immune suppression therapy in tissue or solid organ transplantation or aging or immunesenescence.  
     
     
         12 . The method of  claim 11  wherein one R 4  is in the β-configuration or the α-configuration and is —NH 2 , a substituted amine, a carbamate having the structure —NH—C(O)—O-optionally substituted alkyl or an amide having the structure —NH—C(O)-optionally substituted alkyl, which is optionally selected from —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —N HR PR , —NH—C(O)—H, —NH—C(O)—CH 3 , —NH—C(O)—OCH 3 , —NH—C(O)—OC 2 H 5 , —NH—C(O)—OC 3 H 7  and —NH—C(O)-optionally substituted alkyl or wherein the formula 1 compound is a compound in groups 1 through 52 or an analog of a compound in groups 1 through 52.  
     
     
         13 . The method of  claim 11  wherein the formula 1 compound is 3β-hydroxy-17β-aminoandrost-5-ene, 3β-hydroxy-16α-fluoro-17β-aminoandrost-5-ene, 3β-hydroxy-16β-fluoro-17β-aminoandrost-5-ene, 3β-hydroxy-16,16-difluoro-17β-aminoandrost-5-ene, 3β,16α-dihydroxy-17β-aminoandrost-5-ene, 3β,16β-dihydroxy-17β-aminoandrost-5-ene, 3β-hydroxy-16,16-dimethyl-17β-aminoandrost-5-ene, an ester or carbonate of any of these compounds or an analog of any of the foregoing compounds where the double bond at the 5-6 position is absent and a hydrogen or other R 10  moiety is present at the 5-position in the α- or β-configuration and/or wherein the hydroxyl group (or ester or carbonate analog) at the 3-position is present in the α-configuration.  
     
     
         14 . The method of  claim 11  wherein the formula 1 compound is 3β-hydroxy-17β-aminoandrost-5-ene.  
     
     
         15 . The method of  claim 1  wherein the subject is a human having cystic fibrosis.  
     
     
         16 . The method of  claim 15 , wherein one or more symptoms or syndromes are ameliorated, or wherein the progression of the disease is reduced.  
     
     
         17 . The method of  claim 16 , wherein the one or more symptoms or syndromes are 1, 2, 3 or more of  Staphylococcus  (e.g.,  S. aureus ),  Haemophilus influenzae, Pseudomonas  or  Burkholderia  respiratory tract or lung infection or propensity to develop a detectable infection or colonization, coughing, wheezing, cyanosis, bronchiolitis, bronchospasm, pneumothorax, hemoptysis, pancreatic exocrine insufficiency, bronchiectatic lung disease, atelectasis-consolidation, pulmonary edema, increased lung vascular hydrostatic pressure, increased lung vascular permeability, sinusitis, respiratory insufficiency, bronchial wall or interlobular septa thickening, reduction of forced expiratory volume in 1 second, dyspnea, impaired male fertility, elevated sweat chloride, mucous plugging, tree-in-bud sign, mosaic perfusion pattern, glucose intolerance or abnormal elevation of one or more of IL-4, IL-8, RANTES, neutrophil elastase, eosinophils, macrophages, neutrophils, eosinophil cationic protein or cysteinyl leukotrienes.  
     
     
         18 . The method of  claim 15  wherein the formula 1 compound is 16α-bromoepiandrosterone, 16α-bromoepiandrosterone hemihydrate, 16α-hydroxyepiandrosterone, 16β-hydroxyepiandrosterone, 3α,17β-dihydroxyandrostane, 3β,17β-dihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane, 3α,16β,17β-trihydroxyandrostane, 3β,16α,17β-trihydroxyandrostane, 3β,16β,17β-trihydroxyandrostane, or an ester, carbonate or other analog of any of these compounds that can convert to the compound by metabolism or hydrolysis.  
     
     
         19 . A method to treat or to reduce the severity of a chronic allergy or an atopic disease, or one or more symptoms of the chronic allergy or atopic disease in a subject in need thereof, comprising administering an effective amount of a formula 1 compound of  claim 1 , wherein 
 one R 1  is, or both R 1  together are, —OH, OR PR , —SR PR , —O—Si—(R 13 ) 3 , —COOH, —OSO 3 H, —OPO 3 H, ═O, ═S, an ester, a thioester, a thionoester, 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 or a carbamate, and the other R 1  is independently chosen; and    one R 4  is, or both R 4  together are, —OH, —OR PR , —SR PR , N(R PR ) 2 , —Si—(R 13 ) 3 , —CHO, —CHS, —CN, —SCN, —NO 2 , —NH 2 , —COOH, —OSO 3 H, —OPO 3 H, ═O, ═S, ═N—OH, ═N—O-optionally substituted alkyl, an ester, a thioester, a thionoester, 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 or a carbamate, and the other R 4  is independently chosen.    
     
     
         20 . The method of  claim 19  wherein the compound is 16α-bromoepiandrosterone, 16α-bromoepiandrosterone hemihydrate, 16α-iodoepiandrosterone, 16-oxoepiandrosterone, 16-oxoandrosterone, 3β,16α-dihydroxyandrostane-17-one, 3α,16α-dihydroxyandrostane-17-one, 3β,16β-dihydroxyandrostane-17-one, 3α,16β-dihydroxyandrostane-17-one, 3β,16α,17β-trihydroxyandrostane, 3α,16β,17β-trihydroxyandrostane, 3β,16β,17β-trihydroxyandrostane, 3α,16β,17β-trihydroxyandrostane, or an analog of any of these compounds that is (1) 2-oxa or 11-oxa substituted, (2) substituted at the 7-position with an α-halogen, β-halogen, α-hydroxyl, 1-hydroxyl or oxo moiety, (3) a D-ring homo analog, (4) a 19-nor analog and/or (5) an analog of any of the foregoing compounds that is substituted with an R 10  substituent disclosed herein, e.g., wherein the R 10  is a hydroxyl, thiol, optionally substituted alkyl or a halogen such as fluorine or bromine at the 1-, 2-, 4-, 6-, 9-11-, 12-, 14-, 15- or 16-positions, wherein the R 10 , e.g., the hydroxyl, thiol, optionally substituted alkyl or halogen is present in the α-configuration or the 1-configuration.  
     
     
         21 . The method of  claim 19  wherein the level or activity of IgE in the subject is at least transiently detectably reduced.  
     
     
         22 . The method of  claim 1  wherein the subject is a human who has a sickle cell disease.  
     
     
         23 . The method of  claim 22  wherein the treatment reduces (1) the severity of pain during vascular or microvascular occlusions, (2) the severity of vascular or microvascular occlusions or (3) the frquency of vascular or microvascular occlusions.  
     
     
         24 . The method of  claim 22  wherein the formula 1 compound is administered by an intermittent administration protocol.  
     
     
         25 . The method of  claim 22  wherein one R 1  is, or both R 1  together are, —H, —OH, —OR PR , —SR PR , —O—Si—(R 13 ) 3 , —COOH, —OSO 3 H, —OPO 3 H, ═O, ═S, an ester, a thioester, a thionoester, 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 or a carbamate, and the other R 1  is independently chosen; and 
 one R 4  is, or both R 4  together are, —OH, —OR PR , —SR PR , N(R PR ) 2 , —O—Si—(R 13 ) 3 , —CHO, —CHS, —CN, —SCN, —NO 2 , —NH 2 , —COOH, —OSO 3 H, —OPO 3 H, ═O, ═S, ═N—OH, ═N—O-optionally substituted alkyl, an ester, a thioester, a thionoester, 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 or a carbamate, and the other R 4  is independently chosen.    
     
     
         26 . The method of  claim 25  wherein the compound is 3β,17β-dihydroxyandrost-5-ene, 3β,7β,17β-trihydroxyandrost-5-ene, 3β,17β-dihydroxyandrost-1,5-diene, 3β,7β,17β-trihydroxyandrost-1,5-diene, 3β,17β-dihydroxy-16-haloandrost-5-ene, 3β,7β,17β-trihydroxy-16-haloandrost-5-ene, 16α-fluoro-17-oxoandrost-5-ene, 3α-hydroxy-16α-fluoro-17-oxoandrost-5-ene, 3β-hydroxy-16α-fluoro-17-oxoandrost-5-ene, 3β,17β-dihydroxy-16α-fluoroandrost-5-ene, 3α,17β-dihydroxy-16α-fluoroandrost-5-ene, 16α-bromoepiandrosterone, 16α-bromoepiandrosterone hemihydrate, 16α-iodoepiandrosterone, 16-oxoepiandrosterone, 16-oxoandrosterone, 3β,16α-dihydroxyandrostane-17-one, 3α,16α-dihydroxyandrostane-17-one, 3β,16β-dihydroxyandrostane-17-one, 3α,16β-dihydroxyandrostane-17-one, 3β,16α,17β-trihydroxyandrostane, 3α,16β,17β-trihydroxyandrostane, 3β,16β,17β-trihydroxyandrostane, 3α,16β,17β-trihydroxyandrostane, or an analog of any of these compounds that is (1) 11-oxa substituted or 2-oxa substituted if no double bond is present at the 1-2 position, (2) substituted at the 7-position with an α-halogen, β-halogen, α-hydroxyl, 1-hydroxyl or oxo moiety, (3) a D-ring homo analog, (4) a 19-nor analog and/or (5) an analog of any of the foregoing compounds that is substituted with an R 10  substituent disclosed herein, e.g., wherein the R 10  is a hydroxyl, thiol, optionally substituted alkyl or a halogen such as fluorine or bromine at the 1-, 2-, 4-, 6-, 9-11-, 12-, 14-, 15- or 16-positions, wherein the R 10 , e.g., the hydroxyl, thiol, optionally substituted alkyl or halogen is present in the α-configuration or the p-configuration.  
     
     
         27 . A method to modulate the expression in a cell of the level of or an activity of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more gene products or gene transcripts in the cell, comprising contacting an effective amount of the compound with the cell under suitable conditions and for a sufficient time to detectably modulate the activity or level of the genes, or gene products in the cell, wherein the compound is a compound of any of embodiments 1-9 and the gene products or gene transcripts are selected from USF1, c-Fos, EGR1, Cul1, RIPK2, IκBα, IκBKb, NF-κB1 p50, FCAR, c-Fos/C/EBPβ, RANTES, ICAM1, TSG (TNFAIP6), IL-2 receptor a, GRO2, GRO3, HO1, Jun B, c-Fos/JunB complex, JunB/ATF3 complex, c-Jun, c-Fos/c-Jun complex, ATF-3, MMP1, TSG-6 (TNFAIP3), AP-1, EGR1, TGFβ, ATF-3/c-Jun complex, c-Fos, MMP3, IL-8, STAT5A, STAT5B, CDKN1A, IFNγ receptor 2 (IFNγR 2 ), T-bet, C reactive protein, immunoglobulin E, an AP-1 family protein, GATA-3, Jak2, Tyk2, stat1, stat3, stat4, stat5, stat6, MIP-1a, MIP-2, IP-10, MCP-1, TNF-α, TNF-β, LT-β, IFN-α, IFN-β, TGF-β1, NF-κB, IL-1α, IL-1β, IL-4, IL-6, IL-10, IL-12 receptor 01, IL-12p35, IL-12p40, IL-23, IL-23 receptor, Nrf2, a Maf protein, a thioredoxin, NQO1, GST, HO 1, SOD2, the catalytic subunit of γGCS, the regulatory subunit of γGCS and xCT.  
     
     
         28 . The method of  claim 27  wherein there is a detectable increase in the level of the mRNA, the protein or one or more biological activities associated with the gene product.  
     
     
         29 . The method of  claim 27  wherein the formula 1 compound is 16α-bromo-3β-hydroxy-5α-androstan-17-one, 16α-bromo-3β-hydroxy-5α-androstan-17-one hemihydrate, 16α-fluoro-3β-hydroxy-5α-androstan-17-one, 16α-chloro-3β-hydroxy-5α-androstan-17-one, 160-bromo-3β-hydroxy-5α-androstan-17-one, 16β-fluoro-3β-hydroxy-5α-androstan-17-one, 160-chloro-3β-hydroxy-5α-androstan-17-one, 16α, 3β-dihydroxy-5α-androstan-17-one, 16β,3β-dihydroxy-5α-androstan-17-one, 16α, 3α-dihydroxy-5α-androstan-17-one, 16β,3α-dihydroxy-5α-androstan-17-one, 16α-bromo-3β-hydroxy-5α-androstan-17-one hemihydrate, 3α-hydroxy-16α-fluoroandrostane-17-one, 3β-hydroxy-16α-fluoroandrostane-17-one, 17α-hydroxy-16α-fluoroandrostane-3-one, 17β-hydroxy-16α-fluoroandrostane-3-one, 17α-hydroxy-16α-fluoroandrostane-4-one, 17β-hydroxy-16α-fluoroandrostane-4-one, 17α-hydroxy-16α-fluoroandrostane-6-one, 17β-hydroxy-16α-fluoroandrostane-6-one, 17α-hydroxy-16α-fluoroandrostane-7-one, 17β-hydroxy-16α-fluoroandrostane-7-one, 17α-hydroxy-16α-fluoroandrostane-11-one, 17β-hydroxy-16α-fluoroandrostane-11-one, 16α-fluoroandrost-5-ene-17-one, 7α-hydroxy-16α-fluoroandrost-5-ene-17-one, 7β-hydroxy-16α-fluoroandrost-5-ene-17-one, 4α-hydroxy-16α-fluoroandrost-5-ene-17-one, 3α-hydroxy-16α-fluoroandrost-5-ene-17-one, 3β-hydroxy-16α-fluoroandrost-5-ene-17-one, 4β-hydroxy-16α-fluoroandrost-5-ene-17-one, 6α-hydroxy-166α-fluoroandrost-5-ene-17-one, 60-hydroxy-16α-fluoroandrost-5-ene-17-one, 11α-hydroxy-16α-fluoroandrost-5-ene-17-one, 11-hydroxy-16α-fluoroandrost-5-ene-17-one, 4α,17β-dihydroxy-16α-fluoroandrost-5-ene, 4β,17β-dihydroxy-16α-fluoroandrost-5-ene, 6α,17β-dihydroxy-16α-fluoroandrost-5-ene, 6β,17β-dihydroxy-16α-fluoroandrost-5-ene, 11α,17β-dihydroxy-16α-fluoroandrost-5-ene, 1β,17β-dihydroxy-16α-fluoroandrost-5-ene, 4α,17α-dihydroxy-16α-fluoroandrost-5-ene, 4β,17α-dihydroxy-16α-fluoroandrost-5-ene, 6α,17α-dihydroxy-16α-fluoroandrost-5-ene, 6β,17α-dihydroxy-16α-fluoroandrost-5-ene, 11α,17α-dihydroxy-16α-fluoroandrost-5-ene, 11β,17α-dihydroxy-16α-fluoroandrost-5-ene, 7α,17β-dihydroxy-16α-fluoroandrost-5-ene, 7β,17β-dihydroxy-16α-fluoroandrost-5-ene, 3α,17β-dihydroxy-16α-fluoroandrost-5-ene, 3β,17β-dihydroxy-16α-fluoroandrost-5-ene, 3α,17α-dihydroxy-16α-fluoroandrost-5-ene, 3β,17α-dihydroxy-16α-fluoroandrost-5-ene, 1α,17β-dihydroxy-16α-fluoroandrost-5-ene, 1β,17β-dihydroxy-16α-fluoroandrost-5-ene, 2α,17β-dihydroxy-16α-fluoroandrost-5-ene, 2β,17β-dihydroxy-16α-fluoroandrost-5-ene, 12α,17β-dihydroxy-16α-fluoroandrost-5-ene, 12β,17β-dihydroxy-16α-fluoroandrost-5-ene, 1α,17α-dihydroxy-16α-fluoroandrost-5-ene, 1β,17α-dihydroxy-16α-fluoroandrost-5-ene, 2α,17α-dihydroxy-16α-fluoroandrost-5-ene, 2β,17α-dihydroxy-16α-fluoroandrost-5-ene, 12a, 17α-dihydroxy-16α-fluoroandrost-5-ene, 12β,17α-dihydroxy-16α-fluoroandrost-5-ene, 15α,17β-dihydroxy-16α-fluoroandrost-5-ene, 15β,17β-dihydroxy-16α-fluoroandrost-5-ene, 17β,18-dihydroxy-16α-fluoroandrost-5-ene, 17β,19-dihydroxy-16α-fluoroandrost-5-ene, 15α,17α-dihydroxy-16α-fluoroandrost-5-ene, 15β,17α-dihydroxy-16α-fluoroandrost-5-ene, 17α, 18-dihydroxy-16α-fluoroandrost-5-ene, 17α, 19-dihydroxy-16α-fluoroandrost-5-ene, 16α-fluoroandrost-4-ene-17-one, 7α-hydroxy-16α-fluoroandrost-4-ene-17-one, 71-hydroxy-16α-fluoroandrost-4-ene-17-one, 3α-hydroxy-16α-fluoroandrost-4-ene-17-one, 3β-hydroxy-16α-fluoroandrost-4-ene-17-one, 4α-hydroxy-16α-fluoroandrost-4-ene-17-one, 4β-hydroxy-16α-fluoroandrost-4-ene-17-one, 6α-hydroxy-16α-fluoroandrost-4-ene-17-one, 6β-hydroxy-16α-fluoroandrost-4-ene-17-one, 11α-hydroxy-16α-fluoroandrost-4-ene-17-one, 11β-hydroxy-16α-fluoroandrost-4-ene-17-one, 4α,17β-dihydroxy-16α-fluoroandrost-4-ene, 4β,17β-dihydroxy-16α-fluoroandrost-4-ene, 6α,17β-dihydroxy-16α-fluoroandrost-4-ene, 6β,17β-dihydroxy-16α-fluoroandrost-4-ene, 11α,17β-dihydroxy-16α-fluoroandrost-4-ene, 11β,17β-dihydroxy-16α-fluoroandrost-4-ene, 4α,17α-dihydroxy-16α-fluoroandrost-4-ene, 4β,17α-dihydroxy-16α-fluoroandrost-4-ene, 6α,17α-dihydroxy-16α-fluoroandrost-4-ene, 6β,17α-dihydroxy-16α-fluoroandrost-4-ene, 11α,17α-dihydroxy-16α-fluoroandrost-4-ene, 11β,17α-dihydroxy-16α-fluoroandrost-4-ene, 7α,17β-dihydroxy-16α-fluoroandrost-4-ene, 7β,17β-dihydroxy-16α-fluoroandrost-4-ene, 3α,17β-dihydroxy-16α-fluoroandrost-4-ene, 3β,17β-dihydroxy-16α-fluoroandrost-4-ene, 3α,17α-dihydroxy-16α-fluoroandrost-4-ene, 3β,17α-dihydroxy-16α-fluoroandrost-4-ene, 1α,17β-dihydroxy-16α-fluoroandrost-4-ene, 1β,17β-dihydroxy-16α-fluoroandrost-4-ene, 2α,17β-dihydroxy-16α-fluoroandrost-4-ene, 2β,17β-dihydroxy-16α-fluoroandrost-4-ene, 12α,17β-dihydroxy-16α-fluoroandrost-4-ene, 12β,17β-dihydroxy-16α-fluoroandrost-4-ene, 1α,17α-dihydroxy-16α-fluoroandrost-4-ene, 1β,17α-dihydroxy-16α-fluoroandrost-4-ene, 2α,17α-dihydroxy-16α-fluoroandrost-4-ene, 2β,17α-dihydroxy-16α-fluoroandrost-4-ene, 12α,17α-dihydroxy-16α-fluoroandrost-4-ene, 12β,17α-dihydroxy-16α-fluoroandrost-4-ene, 1 5α,17β-dihydroxy-16α-fluoroandrost-4-ene, 15β,17β-dihydroxy-16α-fluoroandrost-4-ene, 17β,18-dihydroxy-16α-fluoroandrost-4-ene, 17β,19-dihydroxy-16α-fluoroandrost-4-ene, 15α,17α-dihydroxy-16α-fluoroandrost-4-ene, 15β,17α-dihydroxy-16α-fluoroandrost-4-ene, 17α,18-dihydroxy-16α-fluoroandrost-4-ene, 17α,19-dihydroxy-16α-fluoroandrost-4-ene, 3β,17β-dihydroxyandrost-5-ene, 3β-hydroxy-7,17-dioxoandrost-5-ene, 3α-hydroxy-7,17-dioxoandrost-5-ene, 3,17-dioxoandrost-5-ene, 3,17-dioxoandrost-4-ene, 3,17-dioxoandrost-1,4-diene, 3β,7β,17β-trihydroxyandrost-5-ene, 3β,7β,17β-trihydroxyandrostane, 3β,16α-dihydroxy-17-oxoandrostane, 3α,16α-dihydroxy-17-oxoandrostane, 3β,16β-dihydroxy-17-oxoandrostane, 3α,16β-dihydroxy-17-oxoandrostane, 3β,16α,17β-trihydroxyandrostane, 3β,16β,17β-trihydroxyandrostane, 3β,16α,17α-trihydroxyandrostane, 3β,16β,17α-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane, 3α,16β,17β-trihydroxyandrostane or an analog of any of these compounds that is (1) 11-oxa substituted or 2-oxa substituted if no double bond is present at the 1-2 position, (2) substituted at the 7-position with an α-halogen, 1-halogen, α-hydroxyl, 1-hydroxyl or oxo moiety, (3) a D-ring homo analog, (4) a 19-nor analog and/or (5) an analog of any of the foregoing compounds that is substituted with an R 10  substituent disclosed herein, e.g., wherein the R 10  is a hydroxyl, thiol, optionally substituted alkyl or a halogen such as fluorine or bromine at the 1-, 2-, 4-, 6-, 9-11-, 12-, 14-, 15- or 16-positions, wherein the R 10 , e.g., the hydroxyl, thiol, optionally substituted alkyl or halogen is present in the α-configuration or the β-configuration.  
     
     
         30 . A method to treat a cardiovascular condition, an autoimmune condition, a trauma, an unwanted inflammation condition or an unwanted immune response to an allograft or rejection of an allogeneic tissue, organ or cell population comprising administering to a subject having or who may be expected to develope the cardiovascular condition, autoimmune condition, unwanted inflammation condition or the unwanted immune response to an allograft or acute or chronic rejection of an allogeneic tissue, organ or cell population an effective amount of a formula 1 compound of  claim 1 .  
     
     
         31 . The method of  claim 30  wherein the formula 1 compound is a compound in group 1 through group 52 of an analog of any such compound.  
     
     
         32 . The method of  claim 31  wherein the formula 1 compound is a compound in group 1, 2, 3, 14, 17, 26A, 26B, 26C, 26D, 26E, 33A, 33B, 33C, 33D, 33E or 49.  
     
     
         33 . The method of  claim 32  wherein (1) the compound is a compound in groups 1, 2, 3 or 14-3 wherein R 1 , R 2 , R 3  and R 4  are optionally in the β,β,α,β, β,β,β,β or the α,β,α,β configurations respectively or (2) the compound is in group 26A-1, 26A-3, 26A-14-1, 26A-14-2, 26A-14-3, 26A-1, 33A-3, 33A-14-1, 33A-14-2, 33A-14-3, 49-18-14-3, 49-18-14-4 or 49-18-4β-6 and wherein R 1 , R 2 , R 3  and R 4  are optionally in the β,β,α,β, β,β,β,β or the α,β,α,β configurations respectively and the second R 4  moiety is optionally selected from optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl or (3) the compound is in group 17-14-3, 17-14-4 or 17-14-6 and wherein R 1 , R 2 , R 3  and R 4  are optionally in the β,β,α,β, β,β,β,β or the α,β,α,β configurations respectively, R 5  is —CH 3  or —C 2 H 5  and R 6  is —H, —CH 2 OH or —CH 3 .  
     
     
         34 . The method of  claim 30  wherein the cardiovascular condition is arteriosclerosis, atherosclerosis, hypercholesterolemia, hypertriglyceridemia or a hypertension condition such as pulmonary hypertension.  
     
     
         35 . The method of  claim 30  wherein the autoimmune condition or unwanted inflammation is a lupus condition such as systemic lupus erythematosus, rheumatoid arthritis, osteoarthritis or Crohn's disease, inflammatory bowel disease, a scleroderma condition or a vasiculitis such as a giant cell arteritis, polyarteritis nodosa or Kawasaki's disease.  
     
     
         36 . The method of  claim 34  wherein the trauma is a bone fracture, a chemical or thermal burn, a hemorrhage or an infarction such as a cerebral infarction.  
     
     
         37 . The method of  claim 30  wherein the subject is a human or a primate.