Steroid compounds with a c17-alkyl side chain and an aromatic a-ring for use in therapy

Abstract

Formula (I) in which: R 1 and R 2 , which may be the same or different, each represents a lower alkyl, alkenyl or alkynyl group; R 3 represents a methyl group having α- or β-configuration; R 4 represents a hydrogen atom or an etherifying or esterifying group; R 5 represents a hydrogen atom, a hydroxyl group or a lower alkoxy group; X represents a group OR 4 , or a group NR 6 R 7 wherein R 6 represents a hydrogen atom, an aliphatic or araliphatic group, or an acyl group comprising an aliphatic, araliphatic or aryl group linked to the nitrogen atom by way of a carbonyl group; and R 7 is a hydrogen atom or a lower alkyl group; Y represents a lower alkylene, alkenylene or alkynylene group optionally substituted by a hydroxyl, etherified hydroxyl or esterified hydroxyl group; exhibit potent effects on modulation of cell growth and differentiation, while having low calcaemic activity.

1 - 21 . (canceled)  
     
     
         22 . A method of treatment of a human or animal subject for a purpose selected from the group consisting of management of neoplastic disease, burn management, and treatment of autoimmune disease, host-graft reaction, transplant rejection, inflammatory diseases, neoplasias or hyperplasias, which method comprises administering to said subject a therapeutically effective amount of a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       in which: 
 R 1  and R 2 , which may be the same or different, each represents a lower alkyl, alkenyl or alkynyl group;  
 R 3  represents a methyl group having α- or β-configuration;  
 R 4  represents a hydrogen atom, a lower alkyl group or a metabolically labile etherifying or esterifying group;  
 R 5  represents a hydrogen atom, a hydroxyl group or a lower alkoxy group;  
 X represents a group OR 4 , wherein R 4  is as defined above, or a group NR 6 R 7  wherein R 6  represents a hydrogen atom, an aliphatic or araliphatic organic group, or an acyl group comprising an aliphatic, araliphatic or aryl organic group linked to the nitrogen atom by way of a carbonyl group; and R 7  is a hydrogen atom or a lower alkyl group;  
 Y represents a lower alkylene, alkenylene or alkynylene group optionally substituted by a hydroxyl group which in turn is optionally substituted by a metabolically labile etherifying or esterifying group; and  
 the dotted lines signify that double bonds may be present at the 16(17)-position and/or either at the 6(7)- and 8(9)-positions or at the 7(8)-position.  
 
     
     
         23 . The method of  claim 22  wherein R 1  and R 2  in formula (I) are independently selected from C 1-6  alkyl groups, C 2-7  alkenyl groups and C 2-7  alkynyl groups.  
     
     
         24 . The method of  claim 23  wherein R 1  and R 2  in formula (I) are straight chain groups.  
     
     
         25 . The method of  claim 23  wherein R 1  and R 2  in formula (I) are selected from methyl, ethyl and propargyl groups.  
     
     
         26 . The method of  claim 22  wherein R 4  in formula (I) is a hydrogen atom, a C 1-6  alkyl group optionally interrupted by one or more oxygen atoms or substituted by a lower cycloalkyl group, a C 1-6  alkanoyl group, a C 1-6  alkane sulphonyl or halogenated methane sulphonyl group, or an arene sulphonyl group.  
     
     
         27 . The method of  claim 26  wherein R 4  in formula (I) is a hydrogen atom.  
     
     
         28 . The method of  claim 22  wherein R 5  in formula (I) represents a hydrogen atom or a methoxy group.  
     
     
         29 . The method of  claim 22  wherein X in formula (I) represents a hydroxyl group or a group of formula NR 6 R 7  wherein: 
 R 6  is a C 1-6  alkyl group, C 6-12  carbocyclic aryl C 1-4  alkyl group, C 1-6  alkanoyl group, C 6-2  carbocyclic aryl.    C 2-5  alkanoyl group, C 7-13  carbocyclic aroyl group or any of the preceding groups substituted by one or more halo, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  alkanoyl, C 1-4  alkylamino, di(C 1-4  alkyl)amino, nitro, carbamoyl or C 1-4  alkanoylamino substituents; and    R 7  is a hydrogen atom or a C 1-6  alkyl group.    
     
     
         30 . The method of  claim 29  wherein X in formula (I) represents a hydroxyl, amino, methylamino, ethylamino, N-ethyl-N-methylamino, acetylamino, benzamido or phenylacetylamino group.  
     
     
         31 . The method of  claim 22  wherein Y in formula (I) contains up to 7 carbon atoms and up to 3 multiple bonds.  
     
     
         32 . The method of  claim 31  wherein Y in formula (I) is a straight chain C 2-6  group.  
     
     
         33 . The method of  claim 22  wherein Y in formula (I) is substituted by an optionally metabolically labilely etherified or esterified hydroxyl group positioned α-, β- or γ- to the group —C(R 1 )(R 2 ).X or α- to any triple bond present in the group Y.  
     
     
         34 . The method of  claim 31  wherein Y in formula (I) is selected from ethylene, trimethylene, tetramethylene, vinylene, buta-1,3-dienylene, prop-2-ynylene and 1-hydroxyprop-2-ynylene.  
     
     
         35 . The method of  claim 22  wherein the compound of formula (I) is one in which: 
 R 1  and R 2  may be the same or different and each represents a lower alkyl group;    R 5  represents a hydrogen atom; and    X represents a group NR 6 R 7  wherein R 7  is hydrogen.    
     
     
         36 . The method of  claim 22  wherein the compound of formula (I) is selected from the group consisting of: 
 25-acetylamino-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;    25-ethylamino-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;    25-methylamino-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;    25-dimethylamino-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;    25-(N-ethyl-N-methylamino)-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;    25-acetylamino-3-methoxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;    25-acetylamino-3-ethoxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;    25-acetylamino-3-isobutoxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;    25-benzamido-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;    25-phenylacetylamino-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;    25-acetylamino-3-hydroxy-24-homo-19-nor-cholest-1,3,5(110)-triene;    3,24-dihydroxy-24-propargyl-19-26,27-trisnor-cholest-1,3,5(10)-triene;    2-methoxy-3,24-dihydroxy-24-propargyl-19,26,27-trisnor-cholesta-1,3,5(10)-triene;    3,24-dihydroxy-20-epi-24-propargyl-19,26,27-trisnor-cholest-1,3,5(110)-triene;    3,24-dihydroxy-24,24-bispropargyl-19-nor-chol-1,3,5(10),22-tetraene;    2-methoxy-3,24-dihydroxy-24,24-bispropargyl-19-nor-chol-1,3,5(10),22-tetraene;    3,24-dihydroxy-20-epi-24,24-bispropargyl-19-nor-chol-1,3,5(10),22-tetraene;    3-hydroxy-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne;    2-methoxy-3-hydroxy-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne;    3-hydroxy-20-epi-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne;    3-hydroxy-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(10)-triene;    2-methoxy-3-hydroxy-25-amino-26,27-bishomo-19-nor-cholesta-1,3,5(10)-triene;    3-hydroxy-20-epi-25-amino-26,26-bishomo-19-nor-cholesta-1,3,5(10)-triene;    3-hydroxy-25-acetylamino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne;    2-methoxy-3-hydroxy-25-acetylamino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne;    3-hydroxy-20-epi-25-acetylamino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne;    3,22-dihydroxy-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(110)-trien-23-yne;    2-methoxy-3,22-dihydroxy-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(110)-trien-23-yne;    3,22-dihydroxy-20-epi-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(1,0)-trien-23-yne;    2-methoxy-3-hydroxy-24-homo-25-acetylamino-19-nor-cholest-1,3,5(10),16-tetraene;    2-methoxy-3-hydroxy-24-homo-25-amino-19-nor-cholest-1,3,5(10),16-tetraene;    2-methoxy-3-hydroxy-25-acetylamino-19-nor-cholest-1,3,5(10),16-tetraene;    2-methoxy-3-hydroxy-25-amino-19-nor-cholest-1,3,5(10),16-tetraene;    3-hydroxy-24-homo-25-acetylamino-19-nor-cholest-1,3,5(10),6,8,16-hexaene;    3-hydroxy-24-homo-25-amino-19-nor-cholest-1,3,5(10),6,8,16-hexaene;    3,25-dihydroxy-19-nor-cholest-1,3,5(10)-trien-23-yne;    3,25-dihydroxy-19-nor-cholest-1,3,5(110)-triene;    2-methoxy-3,25-dihydroxy-19-nor-cholest-1,3,5(110)-trien-23-yne;    3,25-dihydroxy-20-epi-19-nor-cholest-1,3,5(110)-trien-23-yne;    2-methoxy-3,25-dihydroxy-19-nor-cholest-1,3,5(110)-triene;    3,25-dihydroxy-20-epi-19-nor-cholest-1,3,5(110)-triene;    3,25-dihydroxy-24,24a-bishomo-19-nor-cholest-1,3,5(10),22,24(24a)-pentaene;    25-amino-3-hydroxy-20-epi-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;    25-acetylamino-3-hydroxy-20-epi-19-nor-cholest-1,3,5(10),16-tetraene;    25-amino-3-hydroxy-20-epi-19-nor-cholest-1,3,5(10),16-tetraene;    25-acetylamino-3-hydroxy-20-epi-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;    3-hydroxy-24-homo-25-acetylamino-19-nor-cholest-1,3,5(10),6,16-pentaene; and    3-hydroxy-24-homo-25-amino-19-nor-cholest-1,3,5(10),6,16-pentaene.