3-Nitrogen-6,7-dioxygen steroids and uses related thereto

Abstract

A compound of the formula and pharmaceutically acceptable salts, solvates, stereoisomers and prodrugs thereof, in isolation or in mixture, wherein, independently at each occurrence: R 1 and R 2 are selected from hydrogen, oxygen so as to form nitro or oxime, amino, sulfate, and sulfonic acid, and organic groups having 1-30 carbons and optionally containing 1-6 heteroatoms selected from nitrogen, oxygen, phosphorous, silicon, and sulfur, where R 1 and R 2 may, together with the N to which they are both bonded, form a heterocyclic structure that may be part of an organic group having 1-30 carbons and optionally containing 1-6 heteroatoms selected from nitrogen, oxygen and silicon, and where R 1 may be a 2, or 3 atom chain to numeral 2 so that —N—R 1 — forms part of a fused bicyclic structure to ring A; R 3 and R 4 are selected from direct bonds to 6 and 7 respectively so as to form carbonyl groups, hydrogen, or a protecting group such that R 3 and/or R 4 is part of hydroxyl or carbonyl protecting group; numerals 1 through 17 each represent a carbon having substitution as described. The compounds may be formulated into pharmaceutical compositions, and used in the treatment and/or prevention of various conditions, including inflammation, asthma, an allergic disease, chronic obstructive pulmonary disease, atopic dermatitis, solid tumors, AIDS, ischemia, and cardiac arrhythmias.

1 . A compound of the formula  
     
       
         
         
             
             
         
       
       and pharmaceutically acceptable salts, solvates, stereoisomers and prodrugs thereof, in isolation or in mixture, where independently at each occurrence:  
       R 1  and R 2  are selected from hydrogen, oxygen so as to form nitro or oxime, amino, —SO 3 —R, and organic groups having 1-30 carbons and optionally containing 1-6 heteroatoms selected from nitrogen, oxygen, phosphorous, silicon, and sulfur, where R 2  may be a direct bond to numeral 3, or R 1  and R 2  may, together with the N to which they are both bonded, form a heterocyclic structure that may be part of an organic group having 1-30 carbons and optionally containing 1-6 heteroatoms selected from nitrogen, oxygen and silicon; or R 1  may be a 2 or 3 atom chain to numeral 2 so that —N—R 1 — forms part of a fused bicyclic structure to ring A;  
       R 3  and R 4  are selected from direct bonds to 6 and 7 respectively so as to form carbonyl groups, hydrogen, or a protecting group such that R 3  and/or R 4  is part of hydroxyl or carbonyl protecting group;  
       numerals 1 through 17 each represent a carbon, where carbons at numerals 1, 2, 4, 11, 12, 15, 16 and 17 may be independently substituted with 
 (a) one of: ═O, ═C(R 5 )(R 5 ), ═C═C(R 5 )(R 5 ), —C(R 5 )(R 5 )(C(R 5 )(R 5 )) n — and —(O(C(R 5 )(R 5 )) n O)— wherein n ranges from 1 to about 6; or  
 (b) two of the following, which are independently selected: —X, —N(R 1 )(R 2 ), —R 5  and —OR 6 ;  
 
       and where carbons at numerals 5, 8, 9, 10, 13 and 14 may be independently substituted with one of —X, —R 5 , —N(R 1 )(R 2 ) or —OR 6 ;  
       in addition to the —OR 3  and —OR 4  groups as shown, each of carbons 6 and 7 may be independently substituted with one of —X, —N(R 1 )(R 2 ), —R 5  or —OR 6 ;  
       each of rings A, B, C and D is independently fully saturated, partially saturated or fully unsaturated;  
       R 5  at each occurrence is independently selected from H, X, 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 5  groups may together form a ring with the carbon atom to which they are both bonded;  
       R 6  is H or a protecting group such that —OR 6  is a protected hydroxyl group, where vicinal —OR 6  groups may together form a cyclic structure that protects vicinal hydroxyl groups, and where geminal —OR 6  groups may together form a cyclic structure that protects a carbonyl group; and  
       X represents fluoride, chloride, bromide and iodide.  
     
   
   
       2 . The compound of  claim 1  wherein 
 numerals 1 through 16 each represent a carbon, where carbons at numerals 1, 2, 4, 1, 12, 15 and 16 may be independently substituted with 
 (a) one of: ═O, ═C(R 5 )(R 5 ), ═C═C(R 5 )(R 5 ), —C(R 5 )(R 5 )(C(R 5 )(R 5 )) n — and —(O(C(R 5 )(R 5 )) n O)— wherein n ranges from 1 to about 6; or  
 (b) two of the following, which are independently selected: —X, —N(R 1 )(R 2 ), —R 5  and —OR 6 ; and  
   numeral 17 represents a carbon substituted with 
 (a) one of: ═C(R 5a )(R 5a ), ═C═C(R 5a )(R 5a ), and —C(R 5a )(R 5a )(C(R 5a )(R 5a )) n — wherein n ranges from 1 to about 6; or  
 (b) two of the following, which are independently selected: —X, —N(R 1 )(R 2 ) and —R 5a ;  
 where R 5a  at each occurrence is independently selected from H, X, and C 1-30  organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, silicon and sulfur; where two geminal R 5  groups may together form a ring with the carbon atom to which they are both bonded.  
   
   
   
       3 . The compound of  claim 2  wherein R 5a  at each occurrence is independently selected from C 1-30  hydrocarbon, C 1-30  halocarbon, C 1-30  hydrohalocarbon, H, and X.  
   
   
       4 . The compound of  claim 2  wherein R 5a  at each occurrence is independently selected from C 1-10  hydrocarbon, C 1-10  halocarbon, C 1-10  hydrohalocarbon, H, and X.  
   
   
       5 .- 7 . (canceled)  
   
   
       8 . The compound of  claim 1  wherein 
 R 1  and R 2  are hydrogen;    R 3  and R 4  are selected from direct bonds to 6 and 7 respectively so as to form carbonyl groups, hydrogen, or a protecting group such that R 3  and/or R 4  is part of hydroxyl or carbonyl protecting group; and in addition to the —OR 3  and —OR 4  groups as shown, each of carbons 6 and 7 is substituted with hydrogen unless precluded because —OR 3  or —OR 4  represent a carbonyl group;    carbons at numerals 1, 2, 4, 11, 12, 15 and 16 are each substituted with two hydrogens unless said carbon is part of an unsaturated bond;    carbons at numerals 5, 8, 9 and 14 are each substituted with one hydrogen unless said carbon is part of an unsaturated bond;    carbon at numeral 10 is substituted with methyl;    carbon at number 13 is substituted with methyl unless it is part of an unsaturated bond;    carbon at numeral 17 is substituted with 
 (a) one of: ═O, ═C(R 5 )(R 5 ), ═C═C(R 5 )(R 5 ), —C(R 5 )(R 5 )(C(R 5 )(R 5 )) n — and —(O(C(R 5 )(R 5 )) n O)— wherein n ranges from 1 to about 6; or  
 (b) two of the following, which are independently selected: —X, —N(R 1 )(R 2 ), —R 5  and —OR 6 ;  
   each of rings A, B, C and D is independently fully saturated, partially saturated or fully unsaturated;    R 5  at each occurrence is independently selected from H, X, 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 5  groups may together form a ring with the carbon atom to which they are both bonded;    R 6  is H or a protecting group such that —OR 6  is a protected hydroxyl group, where vicinal —OR 6  groups may together form a cyclic structure that protects vicinal hydroxyl groups, and where geminal —OR 6  groups may together form a cyclic structure that protects a carbonyl group; and    X represents fluoride, chloride, bromide and iodide.    
   
   
       9 .- 16 . (canceled)  
   
   
       17 . The compound of  claim 1  wherein the carbon at numeral 17 is substituted with ═C(R 5 )(R 5 ) and R 5  is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6  hydroxyalkyl, and —CO 2 —C 1-6 alkyl; wherein the carbon at numeral 17 is substituted with C 1-6 alkyl or C 1-6 haloalkyl; or wherein the carbon at numeral 17 is substituted with —OR 6  or ═O, wherein R 6  is hydrogen.  
   
   
       18 . The compound of  claim 1  wherein the carbon at numeral 17 is substituted with C 1-6 alkyl or C 1-6 haloalkyl.  
   
   
       19 . The compound of  claim 1  wherein the carbon at numeral 17 is substituted with —OR 6  or ═O, wherein R 6  is hydrogen.  
   
   
       20 . The compound of  claim 1  wherein R 1  is selected from —C(═O)—R 7 , —C(═O)NH—R 7 ; —SO 2 —R 7 ; wherein R 7  is selected from alkyl, heteroalkyl, aryl and heteroaryl.  
   
   
       21 . The compound of  claim 20  wherein R 7  is selected from C 1-10 hydrocarbyl; or biotin.  
   
   
       22 .- 23 . (canceled)  
   
   
       24 . The compound of  claim 1  wherein R 1  is hydrogen and R 2  comprises a carbocycle.  
   
   
       25 .- 26 . (canceled)  
   
   
       27 . The compound of  claim 1  wherein R 1  is hydrogen and R 2  is a C 1-10 hydrocarbyl or heteroalkyl.  
   
   
       28 .- 29 . (canceled)  
   
   
       30 . The compound of  claim 1  wherein R 1  is hydrogen and R 2  is —CH 2 —R 7  wherein R 7  is selected from alkyl, heteroalkyl, aryl and heteroaryl.  
   
   
       31 . (canceled)  
   
   
       32 . The compound of  claim 1  wherein each of R 1  and R 2  is hydrogen.  
   
   
       33 . The compound of  claim 1  wherein each of R 3  and R 4  is hydrogen.  
   
   
       34 .- 37 . (canceled)  
   
   
       38 . The compound of  claim 1  wherein —N(R 1 )(R 2 ) is in a salt form and the salt is a halogen or acetate salt.  
   
   
       39 .- 40 . (canceled)  
   
   
       41 . The compound of  claim 1  wherein at least one of the carbons at numerals 10 and 13 are substituted with methyl.  
   
   
       42 .- 52 . (canceled)  
   
   
       53 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier, excipient or diluent.  
   
   
       54 . A method of treating inflammation asthma allergic disease, allergic disease, chronic obstructive pulmonary disease, atopic dermatitis, solid tumours, AIDS, ischemia reperfusion injury or cardiac arrhythias comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 .  
   
   
       55 .- 63 . (canceled)