Compositions and treatment methods

Abstract

The invention relates to the use of compounds to treat a number of conditions, such as thrombocytopenia, neutropenia or the delayed effects of radiation therapy. Compounds that can be used in the invention include methyl-2,3,4-trihydroxy-1-O-(7,17-dioxoandrost-5-ene-3β-yl)-β-D-glucopyranosiduronate, 16α,3α-dihydroxy-5α-androstan-17-one or 3,7,16,17-tetrahydroxyandrost-5-ene, 3,7,16,17-tetrahydroxyandrost-4-ene, 3,7,16,17-tetrahydroxyandrost-1-ene or 3,7,16,17-tetrahydroxyandrostane that can be used in the treatment method.

1 . A parenteral formulation comprising castor oil and one, two, three or more excipients other than castor oil, and (2) a compound having the structure  
       
         
           
           
               
               
           
         
         wherein,  
         R 1  is —H, —OH, —SH, ═O, ═S, ester, ether, thioester or thioether;  
         R 2  is —H, —OH, —SH, ═O, ═S, optionally substituted alkyl, ester, ether, thioester or thioether;  
         R 3  is —H, —F, —Cl, —Br, —I, —OH, —SH, ═O, ═S, optionally substituted alkyl, ester, ether, thioester or thioether;  
         one R 4  is —OH, —SH, ═O, ═S, ester, ether, thioester or thioether;  
         the other R 4  is —H or optionally substituted alkyl;  
         R 5  is —H, —CH 2 OH or —CH 3 ;  
         R 6  is —H, —CH 2 OH or —CH 3 ;  
         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 10  independently are —H, —F, —Cl, —Br, —I, —OH, —SH, ═O, ═S, optionally substituted alkyl, ester, ether, thioester or thioether; and  
         R PR  independently is —H or a protecting group, wherein the parenteral formulation contains less than about 0.3% v/v water.  
       
     
     
         2 . The parenteral formulation of  claim 1  wherein the excipients are selected from the group consisting of propylene glycol, PEG100, PEG200, PEG300, PEG400 and benzyl benzoate.  
     
     
         3 . The parenteral formulation of  claim 1  wherein the parenteral formulation contains less than 0.2% v/v water.  
     
     
         4 . The parenteral formulation of  claim 1  wherein the parenteral formulation contains one excipient other than castor oil, which excipient is benzyl benzoate.  
     
     
         5 . The parenteral formulation of  claim 4  wherein R 7 , R 8  and R 9  independently are —CH 2 , —O—, —S—, —NH—, or —C(R 10 ) 2 —.  
     
     
         6 . The parenteral formulation of  claim 5  wherein the compound has the structure  
       
         
           
           
               
               
           
         
       
     
     
         7 . The parenteral formulation of  claim 5  wherein the compound has the structure  
       
         
           
           
               
               
           
         
       
     
     
         8 . The parenteral formulation of  claim 5  wherein the compound has the structure  
       
         
           
           
               
               
           
         
         wherein R 4  is —OH or a C 2-20  ester.  
       
     
     
         9 . The parenteral formulation of  claim 8  wherein the C 2-20  ester is —O—C(O)—C1-C8 optionally substituted alkyl, —O—CH(OH)—C1-C8 optionally substituted alkyl, —O—C(O)—(CH 2 ) n  —(CHCH 3 ) m —(CH 2 ) o —CH 3  or —O—C(O)—(CH 2 ) n —(CHC 2 H 5 ) m —(CH 2 ) o —CH 3  where n, m and o independently are 0, 1, 2, 3, 4, 5, 6, 7 or 8.  
     
     
         10 . The parenteral formulation of  claim 8  wherein the C 2-20  ester is —O—C(O)—CH 3 , —O—C(O)—CH 2 CH 3 , —O—C(O)—CH 2 CH 2 CH 3 , —O—C(O)—(CH 2 ) 5 CH 3 , —O—C(O)CH 2 NH 2 , —O—C(O)C(CH 3 )H—NH 2 , —O—C(O)C(CH 2 C 6 H 5 )H—NH 2 , —O—C(O)—CF 3 , —O—C(O)—CH 2 CF 3 , —O—C(O)—(CH 2 ) 3 CF 3 , —O—C(O)—CH 2 —OH, —O—C(O)—(CH 2 ) n —(CHCH 3 ) m —(CH 2 ) n —CH 3  or —O—C(O)—(CH 2 ) n —(CHC 2 H 5 ) m —(CH 2 ) o —CH 3  where n is 5, 6, 7 or 8, m is 0 and o is 3, 4, 5, 6, 7 or 8.  
     
     
         11 . The parenteral formulation of  claim 10  wherein the C 2-20  ester is —O—C(O)—CH 3 , —O—C(O)—(CH 2 ) 5 CH 3  or —O—C(O)—(CH 2 ) n —CHC 2 H 5 ) m —(CH 2 ) n —CH 3  where n is 5, m is 0 and o is 4 and wherein the parenteral formulation contains one excipient other than castor oil, which excipient is benzyl benzoate.  
     
     
         12 . A method to treat or prevent the side-effects of radiation or chemotherapy in a human comprising administering about 4-40 mg/kg/day of the compound of  claim 1  in the parenteral formulation of  claim 1 , wherein the parenteral formulation is optionally administered by intramuscular injection.  
     
     
         13 . The method of  claim 12  wherein the parenteral formulation is administered for 2, 3, 4, 5, 6 or 7 consecutive days, optionally followed by (1) not administering the parenteral formulation for about 14, 28, 42, 56 or 84 consecutive days, (2) administering the parenteral formulation 2, 3, 4, 5, 6 or 7 consecutive days and (3) repeating steps (1) and (2) 0, 1, 2, 3 or more times.  
     
     
         14 . The method of  claim 13  wherein the chemotherapy is a glucocorticoid therapy or wherein the side-effects of the radiation are delayed effects of radiation.  
     
     
         15 . The method of  claim 12  wherein the daily dosage of the compound of  claim 1  is about 200 mg/day, about 400 mg/day, about 500 mg/day or about 1500 mg/day.  
     
     
         16 . A method to treat hypogonadism in a human in need thereof comprising administering about 4-40 mg/kg/day of the compound of  claim 1  in the parenteral formulation of  claim 1 .  
     
     
         17 . The method of  claim 16  wherein the compound has the structure  
       
         
           
           
               
               
           
         
         wherein R 4  is —OH or a C 2-20  ester, optionally selected from the group consisting of —O—C(O)—CH 3 , —O—C(O)—CH 2 CH 3 , —O—C(O)—CH 2 CH 2 CH 3 , —O—C(O)—(CH 2 ) 5 CH 3 , —O—C(O)CH 2 NH 2 , —O—C(O)C(CH 3 )H—NH 2 , —O—C(O)C(CH 2 C 6 H 5 )H—NH 2 , —O—C(O)—CF 3 , —O—C(O)—CH 2 CF 3 , —O—C(O)—(CH 2 ) 3 CF 3  and —O—C(O)—CH 2 —OH.  
       
     
     
         18 . The method of  claim 17  wherein the parenteral formulation is administered for 2, 3, 4, 5, 6 or 7 consecutive days, optionally followed by (1) not administering the parenteral formulation for about 14, 28, 42, 56 or 84 consecutive days, (2) administering the parenteral formulation 2, 3, 4, 5, 6 or 7 consecutive days and (3) repeating steps (1) and (2) 0, 1, 2, 3 or more times.  
     
     
         19 . The method of  claim 17  wherein the C 2-20  ester is —O—C(O)—C1-C8 optionally substituted alkyl, —O—CH(OH)—C1-C8 optionally substituted alkyl, —O—C(O)—(CH 2 ) n —(CHCH 3 ) m (CH 2 ) o —CH 3  or —O—C(O)—(CH 2 ) n —(CHC 2 H 5 ) m —(CH 2 ) o —CH 3  where n, m and o independently are 0, 1, 2, 3, 4, 5, 6, 7 or 8.  
     
     
         20 . The method of  claim 19  wherein the C 2-20  ester is —O—C(O)—CH 3 , —O—C(O)—(CH 2 ) 5 CH 3  or —O—C(O)—(CH 2 ) n —(CHC 2 H 5 ) m —(CH 2 ) o —CH 3  where n is 5, m is 0 and o is 4, wherein the parenteral formulation is optionally administered by intramuscular injection and wherein the parenteral formulation contains one excipient other than castor oil, which excipient is benzyl benzoate.  
     
     
         21 . A compound of formula V  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein  
         (a) R 1  and R 2  are each independently selected from the group consisting of a hydrogen atom and a glucuronide group having the formula  
         
           
             
             
                 
                 
             
           
         
         wherein (i) R 7  is an alkyl ester wherein the alkyl moiety is optionally substituted, and (ii) R 8 , R 9  and R 10  are each —OR 14 , wherein R 14  is a hydrogen atom or a protected hydroxy, optionally substituted alkyl, cycloalkyl; and (iii) at least one of R 1  or R 2  is not hydrogen;  
         (b) R 5  and R 6  are each independently selected from the group consisting of a hydrogen atom, optionally substituted alkyl, hydroxy, and a protected hydroxy; or R 5  and R 6  taken together are a ketone group (═O); and  
         R 12  and R 13  are each independently selected from the group consisting of a hydrogen atom, optionally substituted alkyl, hydroxy, and a protected hydroxy.