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US 6,635,629 B2Granted
3-nitrogen-6,7-dioxygen steroids and uses related thereto
AssigneeInflazyme Pharmaceuticals Ltd.
InventorsJeffery R. Raymond, Claudia E. Kasserra, Yaping Shen
Life of this patent
Estimating the term…
Abstract
A compound of the formula or pharmaceutically acceptable salts, solvates, and stereoisomers thereof, in isolation or in mixture, wherein the R groups are as defined by the present specification. 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.
Claims31
A compound of the formula
- or pharmaceutically acceptable salts, solvates and stereoisomers thereof, in isolation or in mixture, where independently at each occurrence:
- R1 and R2 are hydrogen;
- R3 and R4 are independently selected from direct bonds to the carbons at numerals 6 and 7 respectively so as to form carbonyl groups, hydrogen, or a protecting group such that R3 and/or R4 is part of hydroxyl or carbonyl protecting group;
- and in addition to the —OR3 and —OR4 groups as shown, each of carbons at numerals 6 and 7 is substituted with hydrogen unless precluded because —OR3 or —OR4 represent a carbonyl group;
- numerals 1 through 16 each represent a carbon;
- 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 numeral 13 is substituted with methyl unless it is part of an unsaturated bond;
- and where the carbon at numeral 17 is substituted with
- (a) one of ═C(R5)(R5) and ═C═C(R5)(R5), or
- (b) two of the following, which are independently selected:
- hydrogen, C1-6alkyl and C1-6haloalkyl;
- each of rings A, B, C and D is independently fully saturated, partially saturated or fully unsaturated;
- R5 at each occurrence is independently selected from H, X, and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur;
- and
- X represents fluoride, chloride, bromide and iodide.
14 more elements
A compound of the formula
- or pharmaceutically acceptable salts, solvates and stereoisomers thereof, in isolation or in mixture, where independently at each occurrence:
- R1 and R2 are independently selected from
- hydrogen,
- oxygen so as to form nitro or oxime,
- amino,
- sulfur so as to form —SO3—R or —SO2—R wherein R is selected from H and organic groups having 1-30 carbons optionally containing 1-6 heteroatoms selected from nitrogen, oxygen, phosphorous, silicon and sulfur, and
- organic groups having 1-30 carbons and optionally containing 1-6 heteroatoms selected from nitrogen, oxygen, phosphorous, silicon, and sulfur,
- where R5 may be a direct bond to numeral 3;
- R3 and R4 are independently selected from direct bonds to the carbons at numerals 6 and 7 respectively so as to form carbonyl groups, hydrogen, or a protecting group such that R3 and/or R4 is part of hydroxyl or carbonyl protecting group;
- numerals 1 through 16 each represent a carbon, where carbons at numerals 1, 2, 4, 11, 12, 15 and 16 may be independently substituted with
- (a)one of:
- ═O, ═C(R5)(R5) and ═C═C(R5)(R5);
- or
- (b)two of the following, which are independently selected:
- —X, —N(R1)(R2), —R5 and —OR6;
- and where the carbon at numeral 17 is substituted with ═C(R5)(R5);
- and where carbons at numerals 5, 8, 9, 10, 13 and 14 may be independently substituted with one of —X, —R5, —N(R1)(R2) or —OR6;
- in addition to the —OR3 and —OR4 groups as shown, each of the carbons at numerals 6 and 7 may be independently substituted with one of —X, —N(R1)(R2), —R5 or —OR6;
- each of rings A, B, C and D is independently fully saturated, partially saturated or fully unsaturated;
- each R5 is independently selected from hydrogen, halogen, C1-6alkyl, C1-6hydroxyalkyl, and —CO2—C1-6alkyl;
- R6 is H or a protecting group such that —OR6 is a protected hydroxyl group;
- and
- X represents fluoride, chloride, bromide and iodide.
20 more elements
A compound of the formula
- or pharmaceutically acceptable salts, solvates and stereoisomers thereof, in isolation or in mixture, where independently at each occurrence:
- R1 R2 are independently selected from
- hydrogen,
- oxygen so as to form nitro,
- amino,
- sulfur so as to form —SO3—R or —SO2—R wherein R is selected from H and organic groups having 1-30 carbons optionally containing 1-6 heteroatoms selected from nitrogen, oxygen, phosphorous, silicon and sulfur, and
- organic groups having 1-30 carbons and optionally containing 1-6 heteroatoms selected from nitrogen, oxygen, phosphorous, silicon, and sulfur,
- R3 and R4 are independently selected from direct bonds to the carbons at numerals 6 and 7 respectively so as to form carbonyl groups, hydrogen, or a protecting group such that R3 and/or R4 is part of hydroxyl or carbonyl protecting group;
- numerals 1 through 16 each represent a carbon, where carbons at numerals 1, 2, 4, 11, 12, 15 and 16 may be independently substituted with
- (a) one of:
- ═O, ═C(R5)(R5) and ═C═C(R5)(R5);
- or
- (b)two of the following, which are independently selected:
- —X, —N(R1)(R2), —R5 and —OR6;
- and where the carbon at numeral 17 is substituted with two of the following, which are independently selected:
- hydrogen, C1-6alkyl and C1-6haloalkyl;
- and where carbons at numerals 5, 8, 9, 10, 13 and 14 may be independently substituted with one of —X, —R5, —N(R1)(R2) or —OR6;
- in addition to the —OR3 and —OR4 groups as shown, each of the carbons at numerals 6 and 7 may be independently substituted with one of —X, —N(R1)(R2), —R5 or —OR6;
- each of rings A, B, C and D is independently fully saturated, partially saturated or fully unsaturated;
- at each occurrence is independently selected from H, X, and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur;
- R6 is H or a protecting group such that —OR6 is a protected hydroxyl group;
- and
- X represents fluoride, chloride, bromide and iodide.
20 more elements
A compound of the formula
- or pharmaceutically acceptable salts, solvates and stereoisomers thereof, in isolation or in mixture, where independently at each occurrence:
- R1 is hydrogen and R2 is heteroalkyl selected from C1-10alkyl-W—C1-10alkylene- wherein W is selected from O and NH;
- HO-C1-10alkylene-;
- and HO-C1-10alkylene-W—C1-10alkylene- where W is selected from O and N;
- R3 and R4 independently selected from direct bonds to the carbons at numerals 6 and 7 respectively so as to form carbonyl groups, hydrogen, or a protecting group such that R3 and/or R4 is part of hydroxyl or carbonyl protecting group;
- numerals 1 through 16 each represent a carbon, where carbons at numerals 1, 2, 4, 11, 12, 15 and 16 may be independently substituted with
- (a) one of:
- ═O, ═C(R5)(R5) and ═C═C(R5)(R5);
- or
- (b) two of the following, which are independently selected:
- —X, —N(R1)(R2), —R5 and —OR6;
- and where the carbon at numeral 17 is substituted with
- (a) one of ═C(R5)(R5) and ═C═C(R5)(R5), or
- (b) two of the following, which are independently selected:
- hydrogen, C1-6alkyl and C1-6haloalkyl;
- and where carbons at numerals 5, 8, 9, 10, 13 and 14 may be independently substituted with one of —X, —R5, —N(R1)(R2) or —OR6;
- in addition to the —OR3 and —OR4 groups as shown, each of the carbons at numerals 6 and 7 may be independently substituted with one of —X, —N(R1)(R2), —R5 or —OR6;
- each of rings A, B, C and D is independently fully saturated, partially saturated or fully unsaturated;
- R5 at each occurrence is independently selected from H, X, and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur;
- R6 is H or a protecting group such that —OR6 is a protected hydroxyl group;
- and
- X represents fluoride, chloride, bromide and iodide.
19 more elements
A compound of the formula
- or pharmaceutically acceptable salts, solvates and stereoisomers thereof, in isolation or in mixture, where independently at each occurrence:
- R1 is hydrogen and R2 is —CH2—R7 wherein R7 is selected from alkyl-substituted phenyl;
- halogen-substituted phenyl;
- alkoxy-substituted phenyl;
- aryloxy-substituted phenyl;
- and nitro-substituted phenyl;
- R3 R4 are independently selected from direct bonds to the carbons at numerals 6 and 7 respectively so as to form carbonyl groups, hydrogen, or a protecting group such that R3 and/or R4 is part of hydroxyl or carbonyl protecting group;
- numerals 1 through 16 each represent a carbon, where carbons at numerals 1, 2, 4, 11, 12, 15 and 16 may be independently substituted with
- (a) one of:
- ═O, ═C(R5)(R5) and ═C═C(R5)(R5);
- or
- (b) two of the following, which are independently selected:
- —X, —N(R1)(R2), —R5 and —OR6;
- and where the carbon at numeral 17 is substituted with
- (a) one of ═C(R5)(R5) and ═C═C(R5)(R5), or
- (b) two of the following, which are independently selected:
- hydrogen, C1-6alkyl and C1-6haloalkyl;
- and where carbons at numerals 5, 8, 9, 10, 13 and 14 may be independently substituted with one of —X, —R5, —N(R1)(R2) or —OR6;
- in addition to the —OR3 and —OR4 groups as shown, each of the carbons at numerals 6 and 7 may be independently substituted with one of —X, —N(R1)(R2), —R5 or —OR6;
- each of rings A, B, C and D is independently fully saturated, partially saturated or fully unsaturated;
- R5 at each occurrence is independently selected from H, X, and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur;
- R6 is H or a protecting group such that —OR6 is a protected hydroxyl group;
- and
- X represents fluoride, chloride, bromide and iodide.
21 more elements
A compound of the formula
- or pharmaceutically acceptable salts, solvates, and stereoisomers thereof, in isolation or in mixture, where independently at each occurrence:
- R1 R2 are each hydrogen;
- R3 and R4 are independently selected from a direct bond to the carbon at numerals 6 and 7 respectively so as to form carbonyl groups, hydrogen, or a protecting group such that R3 and/or R4 is part of hydroxyl or carbonyl protecting group;
- numerals 1 through 16 each represent a carbon, where carbons at numerals 1, 2, 4, 11, 12, 15 and 16 may be independently substituted with
- (a) one of:
- ═O, ═C(R5)(R5) and ═C═C(R5)(R5);
- or
- (b) two of the following, which are independently selected:
- —X, —N(R1)(R5), —R5 and —OR6;
- and where the carbon at numeral 17 is substituted with
- (a) one of ═C(R5)(R5) and ═C═C(R5)(R5), or
- (b) two of the following, which are independently selected:
- hydrogen, C1-6alkyl and C1-6haloalkyl;
- and where carbons at numerals 5, 8, 9, 10, 13 and 14 may be independently substituted with one of —X, —R5, —N(R1)(R2) or —OR6;
- in addition to the —OR3 and —OR4 groups as shown, each of the carbons at numerals 6 and 7 may be independently substituted with one of —X, —N(R1)(R2), —R5 or —OR6;
- each of rings A, B, C and D is independently fully saturated, partially saturated or fully unsaturated;
- R5 at each occurrence is independently selected from H, X, and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur;
- R6 is H or a protecting group such that —OR6 is a protected hydroxyl group;
- and
- X represents fluoride, chloride, bromide and iodide.
17 more elements
A compound of the formula
- or pharmaceutically acceptable salts, solvates and stereoisomers thereof, in isolation or in mixture, where independently at each occurrence:
- R1 and R2 are independently selected from
- hydrogen,
- oxygen so as to form nitro,
- amino,
- sulfur so as to form —SO3—R or —SO2—R wherein R is selected from H and organic groups having 1-30 carbons optionally containing 1-6 heteroatoms selected from nitrogen, oxygen, phosphorous, silicon and sulfur, and
- organic groups having 1-30 carbons and optionally containing 1-6 heteroatoms selected from nitrogen, oxygen, phosphorous, silicon, and sulfur;
- R3 and R4 are independently selected from hydrogen and protecting groups such that R3 and/or R4 is part of hydroxyl protecting group;
- numerals 1 through 16 each represent a carbon;
- 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 numeral 13 is substituted with methyl unless it is part of an unsaturated bond;
- and where the carbon at numeral 17 is substituted with
- (a) one of ═C(R5)(R5) and ═C═C(R5)(R5), or
- (b) two of the following, which are independently selected:
- hydrogen, C1-6alkyl and C1-6haloalkyl;
- in addition to the —OR3 and —OR4 groups as shown, each of carbons 6 and 7 may be independently substituted with one of —X, —N(R1)(R2), —R5 or —OR6;
- each of rings A, B, C and D is independently fully saturated, partially saturated or fully unsaturated;
- R5 at each occurrence is independently selected from H and C1-10 hydrocarbons;
- R6 is H or a protecting group such that —OR6 is a protected hydroxyl group;
- and
- X represents fluoride, chloride, bromide and iodide.
20 more elements
A compound of the formula
- or pharmaceutically acceptable salts, solvates and stereoisomers thereof, in isolation or in mixture, where independently at each occurrence:
- R1 and R2 are independently selected from hydrogen, CH3—, CH3(CH2)2—, CH3(CH2)4—, CH3CO—, C6H5CO—(CH3)2CHSO2—, C6H5SO2—, C6H5NHCO—, CH3(CH2)2NHCO—, CH3(CH2)2NH(CH2)2—, (CH3)2N(CH2)2—, HOCH2CH2—, HOCH2(CH2)4—, HOCH2CH2NHCH2CH2—, 3-(CH3)C6H4—, 4-(HO)C6H4—, 4-(H2NSO2)C6H4—, 4-((CH3)2CH)C6H4—CH2—, 2-(F)C6H4—CH2—, 3-(CF3)C6H4—CH2—, 2-(CH3O)C6H4—CH2—, 4-(CF3O)C6H4—CH2—, 3-(C6H5O)C6H4—CH2—, and 3-(NO2)C6H4—CH2—;
- R3 and R4 are selected from direct bonds to the carbons at numerals 6 and 7 respectively so as to form carbonyl groups, hydrogen, or a protecting group such that R3 and/or R4 is part of hydroxyl or carbonyl protecting group;
- numerals 1 through 16 each represent a carbon, where carbons at numerals 1, 2, 4, 11, 12, 15 and 16 may be independently substituted with
- (a) one of:
- ═O, ═C(R5)(R5) and ═C═C(R5)(R5);
- or
- (b) two of the following, which are independently selected:
- —X, —N(R1)(R2), —R5 and —OR6;
- and where the carbon at numeral 17 is substituted with
- (a) one of ═C(R5)(R5) and ═C═C(R5)(R5), or
- (b) two of the following, which are independently selected:
- hydrogen, C1-6alkyl and C1-6haloalkyl;
- and where carbons at numerals 5, 8, 9, 10, 13 and 14 may be independently substituted with one of —X, —R5, —N(R1)(R2) or —OR6;
- in addition to the —OR3 and —OR4 groups as shown, each of the carbons at numerals 6 and 7 may be independently substituted with one of —X, —N(R1)(R2), —R5 or —OR6;
- each of rings A, B, C and D is independently fully saturated, partially saturated or fully unsaturated;
- R5 at each occurrence is independently selected from H, X, and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur;
- R6 is H or a protecting group such that —OR6 is a protected hydroxyl group;
- and
- X represents fluoride, chloride, bromide and iodide.
17 more elements
A compound of the formula
A compound of the formula
A compound of the formula
A compound of the formula
A compound of the formula
- or pharmaceutically acceptable salts, solvates and stereoisomers thereof, in isolation or in mixture, where independently at each occurrence:
- R1 and R2 are hydrogen;
- R3 and R4 are independently selected from hydrogen and protecting groups such that R3 and/or R4 is part of hydroxyl protecting group;
- numerals 1 through 16 each represent a carbon;
- carbons at numerals 1, 2, 4, 11, 12, 15 and 16 are each substituted with two hydrogens;
- 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 numeral 13 is substituted with methyl unless it is part of an unsaturated bond;
- and the carbon at numeral 17 is substituted with ═C(R5)(R5) or two of the following, which are independently selected:
- hydrogen, C1-6alkyl and C1-6haloalkyl;
- each of rings A, B, C and D is independently fully saturated or partially saturated;
- and
- R5 at each occurrence is independently selected from H and C1-10 hydrocarbons.
10 more elements
A compound of the formula
- or pharmaceutically acceptable salts and solvates thereof.
A compound of the formula
- or pharmaceutically acceptable salts and solvates thereof.
A compound of the formula
- or pharmaceutically acceptable salts and solvates thereof.
A compound of the formula
- or pharmaceutically acceptable salts and solvates thereof.
A compound of the formula
- or pharmaceutically acceptable salts and solvates thereof.
A compound of the formula
- or pharmaceutically acceptable salts and solvates thereof.
A compound of the formula
- or pharmaceutically acceptable salts, solvates and stereoisomers thereof, in isolation or in mixture, where independently at each occurrence:
- R1 is hydrogen;
- R2 is hydrogen or C1-10hydrocarbyl;
- R3 and R4 are independently selected from direct bonds to the carbons at numerals 6 and 7 respectively so as to form carbonyl groups, hydrogen, or a protecting group such that R3 and/or R4 is part of hydroxyl or carbonyl protecting group;
- numerals 1 through 16 each represent a carbon, where carbons at numerals 1, 2, 4, 11, 12, 15 and 16 may be independently substituted with
- (a) one of:
- ═O, ═C(R5)(R5) and ═C═C(R5)(R5);
- or
- (b) two of the following, which are independently selected:
- —X, —N(R1)(R2), —R5 and —OR6;
- and where the carbon at numeral 17 is substituted with
- (a) one of ═C(R5)(R5) and ═C═C(R5)(R5), or
- (b) two of the following, which are independently selected:
- hydrogen, C1-6alkyl and C1-6haloalkyl;
- and where carbons at numerals 5, 8, 9, 10, 13 and 14 may be independently substituted with one of —X, —R5, —N(R1)(R2) or —OR6;
- in addition to the —OR3 and —OR4 groups as shown, each of the carbons at numeral 6 and 7 may be independently substituted with one of —X, —N(R1)(R2), —R5 or —OR6;
- each of rings A, B, C and D is independently fully saturated, partially saturated or fully unsaturated;
- R5 at each occurrence is independently selected from H, X, and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur;
- R6 is H or a protecting group such that —OR6 is a protected hydroxyl group;
- and
- X represents fluoride, chloride, bromide and iodide.
18 more elements
A compound of the formula
- or pharmaceutically acceptable salts, solvates and stereoisomers thereof, in isolation or in mixture, where independently at each occurrence:
- R1 is hydrogen;
- R2 is hydrogen or heteroalkyl;
- R3 and R4 are selected from direct bonds to 6 and 7 respectively so as to form carbonyl groups, hydrogen, or a protecting group such that R3 and/or R4 is part of hydroxyl or carbonyl protecting group;
- numerals 1 through 16 each represent a carbon, where carbons at numerals 1, 2, 4, 11, 12, 15 and 16 may be independently substituted with
- (a) one of:
- ═O, ═C(R5)(R5) and ═C═C(R5)(R5);
- or
- (b) two of the following, which are independently selected:
- —X, —N(R1)(R2), —R5 and —OR6;
- and where the carbon at numeral 17 is substituted with ═C(R5)(R5);
- and where carbons at numerals 5, 8, 9, 10, 13 and 14 may be independently substituted with one of —X, —R5, —N(R1)(R2) or —OR6;
- in addition to the —OR3 and —OR4 groups as shown, each of carbons 6 and 7 may be independently substituted with one of —X, —N(R1)(R2), —R5 or —OR6;
- each of rings A, B, C and D is independently fully saturated, partially saturated or fully unsaturated;
- R5 at each occurrence is independently selected from hydrogen, halogen, C1-6alkyl, C1-6hydroxyalkyl, and —CO2—C1-6alkyl;
- R6 is H or a protecting group such that —OR6 is a protected hydroxyl group;
- and
- X represents fluoride, chloride, bromide and iodide.
15 more elements
A compound of the formula
- or pharmaceutically acceptable salts, solvates and stereoisomers thereof, in isolation or in mixture, where independently at each occurrence:
- R1 is hydrogen;
- R2 is hydrogen or heteroalkyl;
- R3 and R4 are selected from direct bonds to 6 and 7 respectively so as to form carbonyl groups, hydrogen, or a protecting group such that R3 and/or R4 is part of hydroxyl or carbonyl protecting group;
- numerals 1 through 16 each represent a carbon, where carbons at numerals 1, 2, 4, 11, 12, 15 and 16 may be independently substituted with
- (a) one of:
- ═O, ═C(R5)(R5) and ═C═C(R5)(R5);
- or
- (b) two of the following, which are independently selected:
- —X, —N(R1)(R2), —R5 and —OR6;
- and where the carbon at numeral 17 is substituted with C1-6alkyl and C1-6haloalkyl;
- and where carbons at numerals 5, 8, 9, 10, 13 and 14 may be independently substituted with one of —X, —R5, —N(R1)(R2) or —OR6;
- in addition to the —OR3 and —OR4 groups as shown, each of carbons 6 and 7 may be independently substituted with one of —X, —N(R1)(R2), —R5 or —OR6;
- each of rings A, B, C and D is independently fully saturated, partially saturated or fully unsaturated;
- R5 at each occurrence is independently selected from H, X, and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur;
- R6 is H or a protecting group such that —OR6 is a protected hydroxyl group;
- and
- X represents fluoride, chloride, bromide and iodide.
15 more elements
Dependencies are inferred from the claim text.