6,7-Oxygenated steroids and uses related thereto

Abstract

Steroid compounds having various oxygen substitution on the steroid nucleus are disclosed. A specific functionality present on many of the steroid compounds is oxygen substitution at both of positions 6 and 7. Thus, certain steroids have oxygen substitution at C6 and C7, and some have specific stereochemistries such as 6α and 7β oxygen substitution, and an alpha hydrogen at the 5 position in addition to having 6α and 7β oxygen substitution. Steroids having 3,4-epoxy functionality are also disclosed. In addition, steroids having C17 pyran and δ-lactone functionality, with oxygen substitution at C6 and C7, or at C15, of the steroid nucleus, are disclosed.

1 . A compound of the formula:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof, wherein: 
 numerals 1 through 17 each represent a carbon;  each of C 1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted according to any of (a) and (b):  
 (a) one of: ═O, ═C(R 4 )(R 4 ), —C(R 4 )(R 4 )(C(R 4 )(R 4 )) n — and —(O(C(R 4 )(R 4 )) n O)— wherein n ranges from 1 to about 6;  
 (b) two of: —X, —R 4  and —OR 1 , each independently selected;  
 each of C5, C6, C7, C8, C9, C10, C13 and C14 is independently substituted with one of —X, —R 4  or —OR 1 ;  
 C17 is substituted according to any of (c), (d), (e), (f), (g), (h) and (i):  
 (c) one of: ═O, ═C(R 4 )(R 4 ), —C(R 4 )(R 4 )(C(R 4 )(R 4 )) n — and —(O(C(R 4 )(R 4 )) n O)— wherein n ranges from 1 to about 6, as long as one of the following conditions i), ii), iii) or iv) apply: 
 i) C5 is substituted with a hydrogen in the alpha configuation, and C3 is not bonded to oxygen, and when C3 is substituted with two hydrogen atoms then C17 is not substituted with either —CH(CH 3 )(CH 2 ) 3 CH(CH 3 ) 2  or —CH(CH 3 )(CH 2 ) 2 C(═O)OCH 3 ;  
 ii) C10 and C13 are not simultaneously substituted with methyl, and when C10 is substituted with methyl, then C14 is not substituted with a methyl, and the A ring is never aromatic;  
 iii) if C3 and C4 are bonded to oxygen atoms, and the C6 —OR 1  substituent has the alpha configuration, and the C7 —OR 1  substituent has the beta configuration, then C17 is not substituted with any of the following:  
                     
 iv) C3 and C4 are each bonded to the same oxygen atom so as to form an oxirane ring, with the proviso that C7 does not have carbonyl substitution when C5 has hydroxyl or —OR 1  substitution;  
 
 (d) a cyclic structure of the formula  
                     
 wherein G is —C(═O)—, —CH(OR 1 )—, —C(R 4 )(OR 1 )— or —C(OR 1 )(OR 1 )—, as long as C3 and C4 are not simultaneously substituted with hydroxyl or protected hydroxyl;  
 (e) two hydrogen atoms, as long as C3 is not substituted with a carbonyl group;  
 the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;  
 R 1  is H or a protecting group such that —OR 1  is a protected hydroxyl group, where vicinal —OR 1  groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal —OR 1  groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of —OR 1  at C6 and C7 represents a carbonyl or protected carbonyl group;  
 R 2 , R 3  and R 4  at each occurrence is independently selected from H and C 1-30  organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R 4  groups may together form a ring with the carbon atom to which they are both bonded; and  
 X represents fluoride, chloride, bromide and iodide.  
 
   
   
       2 . A compound of  claim 1  having the formula  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof, wherein: 
 each of C1, C2, C4, C11, C12, C15 and C16 is independently substituted with  
 (a) one of: ═O, ═C(R 4 )(R 4 ), —C(R 4 )(R 4 )(C(R 4 )(R 4 )) n — and —(O(C(R 4 )(R 4 )) n O)— wherein n ranges from 1 to about 6; or  
 (b) two of the following, which are independently selected: —X, —R 4  and —OR 1 ;  
 each of C5, C8, C9, C10 and C13 is independently substituted with one of —X, —R 4  or —OR 1 ;  
 C3 is substituted with ═C(R 4 )(R 4 ), —C(R 4 )(R 4 )(C(R 4 )(R 4 )) n — and —(O(C(R 4 )(R 4 )) n O)— wherein n ranges from 1 to about 6;  
 each of C6 and C7 is independently substituted with hydrogen or —OR 1 ;  
 C14 is substituted with —X, —OR 1  or —R 4  excluding methyl;  
 the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;  
 R 1  is H or a protecting group such that —OR 1  is a protected hydroxyl group, where vicinal —OR 1  groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal —OR 1  groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of —OR 1  at C6 and C7 represents a carbonyl or protected carbonyl group;  
 R 2 , R 3  and R 4  at each occurrence is independently selected from H and C 1-30  organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R 4  groups may together form a ring with the carbon atom to which they are both bonded; and  
 X represents fluoride, chloride, bromide and iodide.  
 
   
   
       3 . (canceled)  
   
   
       4 . A compound of  claim 1  having the formula  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof, wherein: 
 each of C1, C2, C4, C11, C12, C15, C16 and C17 is independently substituted with  
 (a) one of: ═O, ═C(R 4 )(R 4 ), —C(R 4 )(R 4 )(C(R 4 )(R 4 )) n — and —(O(C(R 4 )(R 4 )) n O)— wherein n ranges from 1 to about 6; or  
 (b) two of the following, which are independently selected: —X, —R 4  and —OR 1 ;  
 each of C8, C9, C10, C13 and C14 is independently substituted with one of —X, —R 4  or —OR 1 ;  
 C3 is substituted with one of ═C(R 4 )(R 4 ) and —C(R 4 )(R 4 )(C(R 4 )(R 4 )) n — wherein n ranges from 1 to about 6;  
 the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;  
 R 1  is H or a protecting group such that —OR 1  is a protected hydroxyl group, where vicinal —OR 1  groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal —OR 1  groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of —OR 1  at C6 and C7 represent a carbonyl or protected carbonyl group;  
 R 4  at each occurrence is independently selected from H and C 1-30  organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur; where two geminal R 4  groups may together form a ring with the carbon atom to which they are both bonded; and  
 X represents fluoride, chloride, bromide and iodide.  
 
   
   
       5 . A compound of  claim 1  having the formula  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof, wherein: 
 each of C1, C2, C3, C4, C11, C12, C15, C16 and C17 is independently substituted with  
 (a) one of: ═O, ═C(R 4 )(R 4 ), —C(R 4 )(R 4 )(C(R 4 )(R 4 )) n — and —(O(C(R 4 )(R 4 )) n O)— wherein n ranges from 1 to about 6; or  
 (b) two of the following, which are independently selected: —X, —R 4  and —OR 1 ;  
 each of C5, C8, C9, C10, C13 and C14 is independently substituted with one of —X, —R 4  or —OR 1 ;  
 with the provisos that (a) C10 and C13 are not simultaneously substituted with methyl, and (b) when C10 is substituted with methyl, then C14 is not substituted with a methyl;  
 the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated with the proviso that the A ring is not aromatic;  
 R 1  is H or a protecting group such that —OR 1  is a protected hydroxyl group, where vicinal —OR 1  groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal —OR 1  groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of —OR 1  at C6 and C7 represent a carbonyl or protected carbonyl group;  
 R 4  at each occurrence is independently selected from H and C 1-30  organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur; where two geminal R 4  groups may together form a ring with the carbon atom to which they are both bonded; and  
 X represents fluoride, chloride, bromide and iodide.  
 
   
   
       6 . A compound of  claim 1  having the formula  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof, wherein: 
 each of C1, C2, C11, C12, C15, and C16 and G17 is independently substituted with  
 (a) one of: ═O, ═C(R 4 )(R 4 ), —C(R 4 )(R 4 )(C(R 4 )(R 4 )) n — and —(O(C(R 4 )(R 4 )) n O)— wherein n ranges from 1 to about 6; or  
 (b) two of the following, which are independently selected: —X, —R 4  and —OR 1 ;  
 C17 is independently substituted with ═O, —C(R 4 )(R 4 )(C(R 4 )(R 4 )) n — and —(O(C(R 4 )(R 4 )) n O)— wherein n ranges from 1 to about 6;  
 each of C5, C9, C10, C13 and C14 is independently substituted with one of —X, —R 4  or —OR 1 ;  
 C8 is substituted with —X or —R 4  and is preferably not bonded directly to oxygen;  
 the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;  
 R 1  is H or a protecting group such that —OR 1  is a protected hydroxyl group, where vicinal —OR 1  groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal —OR 1  groups may together form a cyclic structure which protects a carbonyl group;  
 R 4  at each occurrence is independently selected from H and C 1-30  organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur; where two geminal R 4  groups may together form a ring with the carbon atom to which they are both bonded; and  
 X represents fluoride, chloride, bromide and iodide.  
 
   
   
       7 . A compound of  claim 1  having the formula  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof, wherein: 
 each of C1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted with  
 (a) one of: ═O, ═C(R 4 )(R 4 ), —C(R 4 )(R 4 )(C(R 4 )(R 4 )) n — and —(O(C(R 4 )(R 4 )) n O)— wherein n ranges from 1 to about 6; or  
 (b) two of the following, which are independently selected: —X, —R 4  and —OR 1 ;  
 with the proviso that C3 and C4 are not simultaneously substituted with hydroxyl or protected hydroxyl, and are preferably not simultaneously substituted with oxygen atoms;  
 each of C5, C8, C9, C10, C13 and C14 is independently substituted with one of —X, —R 4  or —OR 1 ;  
 G is —C(═O)—, —CH(OR 1 )—, —C(R 4 )(OR 1 )— or —C(OR 1 )(OR 1 )—;  
 the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;  
 R 1  is H or a protecting group such that —OR 1  is a protected hydroxyl group, where vicinal —OR 1  groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal —OR 1  groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of —OR 1  at C6 and C7 represents a carbonyl or protected carbonyl group;  
 R 4  at each occurrence is independently selected from H and C 1-30  organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R 4  groups may together form a ring with the carbon atom to which they are both bonded; and  
 X represents fluoride, chloride, bromide and iodide.  
 
   
   
       8 . A compound of  claim 1  having the formula  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof, wherein: 
 each of C1, C2, C11, C12, C15, C16 and C17 is independently substituted with  
 (a) one of: ═O, ═C(R 4 )(R 4 ), —C(R 4 )(R 4 )(C(R 4 )(R 4 )) n — and —(O(C(R 4 )(R 4 )) n O)— wherein n ranges from 1 to about 6; or  
 (b) two of the following, which are independently selected: —X, —R 4  and —OR 1 ;  
 each of C5, C8, C9, C10, C13 and C14 is independently substituted with one of —X, —R 4  or —OR 1 ;  
 the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;  
 R 1  is H or a protecting group such that —OR 1  is a protected hydroxyl group, where vicinal —OR 1  groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal —OR 1  groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of —OR 1  at C6 and C7 represents a carbonyl or protected carbonyl group;  
 R 4  at each occurrence is independently selected from H and C 1-30  organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R 4  groups may together form a ring with the carbon atom to which they are both bonded; and  
 X represents fluoride, chloride, bromide and iodide;  
 with the proviso that C7 does not have carbonyl substitution when C5 has hydroxy or —OR 1  substitution.  
 
   
   
       9 . A compound of  claim 1  having a formula selected from:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof, wherein: 
 each of C1, C2, C3, C4, C11, C12 and C16 is independently substituted according to (a) or (b):  
 (a) one of: ═O, ═C(R 4 )(R 4 ), —C(R 4 )(R 4 )(C(R 4 )(R 4 )) n — and —(O(C(R 4 )(R 4 )) n O)— wherein n ranges from 1 to about 6,  
 (b) two of: —X, —R 4  and —OR 1 , each independently selected;  
 C5 is substituted with a hydrogen atom;  
 each of C6, C7, C8, C9, C10, C13 and C14 is independently substituted with one of —X, —R 4  or —OR 1 ; and  
 C17 is substituted according to (c), (d), (e) or (f):  
 (c) two substituents selected from hydrogen, halogen, C 1 -C 30  saturated hydrocarbyl excluding —CH(CH 3 )(CH 2 ) 3 CH(CH 3 ) 2 , halogen substituted C 1 -C 30  saturated hydrocarbyl, C 1 -C 30  unsaturated hydrocarbyl, and halogen substituted C 1 -C 30  unsaturated hydrocarbyl;  
 (d) one substituent selected from ═C(R 4 )(R 4 ) with the proviso that C14 is not substituted with methyl;  
 (e) at least one oxygen atom-containing substituent selected from ═O, —(O(C(R 4 )(R 4 )) n O)— wherein n ranges from 1 to about 6, —OH, and —OR 1 ;  
 (f) at least one nitrogen atom-containing substituent selected from —N(R 4 )(R 4 ) wherein the two R 4  groups may together with the nitrogen atom form one or more rings, so that the nitrogen atom-containing substituent includes nitrogen atom-containing heterocyclic groups; wherein  
 the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;  
 R 1  is H or a protecting group such that —OR 1  is a protected hydroxyl group, where —OR 1  groups bonded to adjacent carbon atoms may together form a cyclic structure which protects both hydroxyl groups;  
 R 4  at each occurrence is independently selected from H and R 5 ;  
 R 5  is a C 1-30  organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur; where two geminal R 1  groups may together form a ring with the carbon atom to which they are both bonded; and  
 X represents fluoride, chloride, bromide or iodide.  
 
   
   
       10 . A compound of  claim 1  having the formula:  
     
       
         
         
             
             
         
       
     
   
   
       11 . A compound of  claim 1  having the formula  
     
       
         
         
             
             
         
       
     
   
   
       12 . A compound of  claim 1  wherein C10 and C13 are each substituted with methyl.  
   
   
       13 . A compound of  claim 1  wherein C11 and C12 are each substituted only with hydrogen.  
   
   
       14 . (canceled)  
   
   
       15 . (canceled)  
   
   
       16 . A compound of  claim 1  wherein C17 is substituted with a substituent selected from carbonyl or protected carbonyl.  
   
   
       17 . A compound of  claim 1  wherein C3 is substituted with a substituent selected from halogen, hydroxyl and protected hydroxyl.  
   
   
       18 . (canceled)  
   
   
       19 . A compound of  claim 1  wherein C3 and C4 are both substituted with oxygen and together form an epoxide, acetal or ketal.  
   
   
       20 . A compound of  claim 1  wherein the A, B, C and D rings are saturated.  
   
   
       21 . A compound of  claim 1  wherein the A ring is unsaturated.  
   
   
       22 . A compound of  claim 1  wherein a double bond is present between C4 and C5.  
   
   
       23 . A compound of  claim 1  wherein C6 and C7 are each substituted with hydrogen.  
   
   
       24 . A compound of  claim 1  wherein C6 and C7 are both substituted with hydroxyl groups.  
   
   
       25 . (canceled)  
   
   
       26 . A pharmaceutical composition comprising a compound of  claim 1  in combination with a pharmaceutically acceptable carrier or diluent.  
   
   
       27 - 60 . (canceled)  
   
   
       61 . A process for treating at least one of asthma, allergy, arthritis and thrombosis comprising administering to a subject in need thereof an effective amount of the compound or salt thereof of according to  claim 1 .  
   
   
       62 . A process for treating at least one of asthma, allergy, arthritis and thrombosis comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of  claim 26 .  
   
   
       63 . (canceled)  
   
   
       64 . A process for treating a condition associated with an elevated level of NFκB activity in a subject, comprising administering to a subject in need thereof an amount of a compound effective to lower the NFκB activity, wherein the compound has the formula of the compounds of  claim 1 .  
   
   
       65 . A process for treating a condition associated with an elevated level of NFκB activity in a subject, comprising administering to a subject in need thereof an amount of a composition effective to lower the NFκB activity, wherein the composition is described in  claim 26 .  
   
   
       66 . (canceled)  
   
   
       67 . A process for introducing an exocyclic olefin group to the C17 position of a 6,7-dioxygenated steroid comprising providing a compound of Formula (10), reacting the compound of Formula (10) with a Wittig reagent of Formula (11) in the presence of a base, to provide an olefin compound of Formula (12)  
     
       
         
         
             
             
         
       
     
     wherein each of the compounds of Formulas (10) and (12) include pharmaceutically acceptable salts and solvates thereof, and wherein: 
 each of C1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted according to any of (a) and (b):  
 (a) one of: ═O, ═C(R 4 )(R 4 ), —C(R 4 )(R 4 )(C(R 4 )(R 4 )) n — and —(O(C(R 4 )(R 4 )) n O)— wherein n ranges from 1 to about 6;  
 (b) two of: —X, —R 4  and —OR 1 , each independently selected;  
 each of C5, C6, C7, C8, C9, C10, C13 and C14 is independently substituted with one of —X, —R 4  or —OR 1 ;  
 R 1  is H or a protecting group such that —OR 1  is a protected hydroxyl group, where vicinal —OR 1  groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal —OR 1  groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of —OR 1  at C6 and C7 represents a carbonyl or protected carbonyl group;  
 Ra, Rb and R 4  at each occurrence is independently selected from H and C 1-30  organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R 4  groups may together form a ring with the carbon atom to which they are both bonded; and  
 X represents fluoride, chloride, bromide and iodide, which is independently selected at each occurrence.  
 
   
   
       68 . The process of  claim 67  wherein the base is selected from sodium t-butoxide, potassium t-butoxide and sodium hydride, and the base is in admixture with an aprotic solvent including toluene, tetrahydrofuran, methylene chloride, dimethylformamide, dimethylsulfoxide, benzene and diethyl ether.  
   
   
       69 . The process of  claim 67  wherein Ra and Rb are independently selected from hydrogen and C 1 -C 7 alkyl, and X is selected from chloride, bromide and iodide.  
   
   
       70 - 72 . (canceled)  
   
   
       73 . A process for a stereocontrolled introduction of a hydroxyl group at C3 of a steroid nucleus, comprising providing a steroid compound of Formula (15) having a carbonyl group at C3, and reducing the carbonyl group to a hydroxyl group with a reducing agent so as to provide at least one compound of Formulas (16) and (17)  
     
       
         
         
             
             
         
       
     
     wherein each of the compounds of Formulas (15), (16) and (17) include pharmaceutically acceptable salts and solvates thereof, and wherein: 
 each of C1, C2, C4, C11, C12, C15, C16 and C17 is independently substituted according to any of (a) and (b):  
 (a) one of: ═O, ═C(R 4 )(R 4 ), —C(R 4 )(R 4 )(C(R 4 )(R 4 )) n — and —(O(C(R 4 )(R 4 )) n O)— wherein n ranges from 1 to about 6;  
 (b) two of: —X, —R 4  and —OR 1 , each independently selected;  
 each of C5, C6, C7, C8, C9, C10, C13 and C14 is independently substituted with one of —X, —R 4  or —OR 1 ;  
 R 1  is H or a protecting group such that —OR 1  is a protected hydroxyl group, where vicinal —OR 1  groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal —OR 1  groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of —OR 1  at C6 and C7 represents a carbonyl or protected carbonyl group;  
 R 4  at each occurrence is independently selected from H and C 1-30  organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R 4  groups may together form a ring with the carbon atom to which they are both bonded; and  
 X represents fluoride, chloride, bromide and iodide.  
 
   
   
       74 . The process of  claim 73  wherein the reducing agent is selected from lithium trisiamylborohydride, lithium tri-sec-butylborohydride and potassium tri-sec-butylborohydride, to provide predominantly the hydroxyl compound of Formula (16).  
   
   
       75 . The process of  claim 73  wherein the reducing agent is selected from sodium borohydride and lithium aluminum hydride, to provide predominantly the hydroxyl compound of Formula (17).  
   
   
       76 . The process of  claim 73  wherein the ratio of Formula (16) to Formula (17) compounds following the reduction is other than 1:1.