Novel phosphorus-containing thyromimetics
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Abstract
The present invention relates to compounds of phosphonic acid-containing T3 mimetics and monoesters thereof, stereoisomers, pharmaceutically acceptable salts, co-crystals, and prodrugs thereof and pharmaceutically acceptable salts and co-crystals of the prodrugs, as well as their preparation and uses for preventing and/or treating metabolic diseases such as obesity, NASH, hypercholesterolemia and hyperlipidemia, as well as associated conditions such as atherosclerosis, coronary heart disease, impaired glucose tolerance, metabolic syndrome x and diabetes.
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Citations
162 Claims
- 1. A compound of Formula I:
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2-31. -31. (canceled)
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32. A compound of Formula II:
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33-59. -59. (canceled)
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60. A compound of Formula III:
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61-91. -91. (canceled)
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92. A compound of Formula VIII:
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93-129. -129. (canceled)
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131-135. -135. (canceled)
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137-151. -151. (canceled)
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153-154. -154. (canceled)
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155. A compound of Formula X:
(Ar1)-G-(Ar2)-T-Xwherein;
Ar1 and Ar2 are aryl groups;
G is an atom or group of atoms that links Ar1 and Ar2 through a single C, S, Se, O, or N atom;
T is an atom or group of atoms linking Ar2 to X through 1-4 contiguous atoms or is absent;
X is a phosphonic acid or phosphonic acid monoester or prodrug thereof;
wherein said compound has a Ki of ≦
150 nM relative to T3;
with the provisos that said compound is not;
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156. A method of improving liver versus heart selectivity of a thyromimetic compound of Formula Y:
(Ar1)-G-(Ar2)-T-Ewherein;
Ar1 and Ar2 are aryl groups;
G is an atom or group of atoms that links Ar1 and Ar2 through a single C, S, Se, O, or N atom;
T is an atom or group of atoms linking Ar2 to E through 1-4 contiguous atoms or is absent;
E is selected from the group consisting of a functional group or moiety with a pKa≦
7.4, a carboxylic acid moiety or an atom or group of atoms containing an O or N that binds the thyroid hormone binding pocket of a TRα
or TRβ
,comprising the step of replacing E with a phosphonic acid or phosphonic acid monoester or prodrug thereof.
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157. A method of increasing the therapeutic index of a thyromimetic compound of Formula Y:
(Ar1)-G-(Ar2)-T-Ewherein;
Ar1 and Ar2 are aryl groups;
G is an atom or group of atoms that links Ar1 and Ar2 through a single C, S, Se, O, or N atom;
T is an atom or group of atoms linking Ar2 to E through 1-4 atoms or is absent;
E is selected from the group consisting of a functional group or moiety with a pKa≦
7.4, a carboxylic acid moiety or an atom or group of atoms containing an O or N that binds the thyroid hormone binding pocket of a TRα
or TRβ
,comprising the step of replacing E with a —
P(O)(OH)2 or prodrug thereof.
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158. A method of designing a thyromimetic compound with improved liver versus heart selectivity comprising the steps of:
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obtaining a molecular formula for a thyromimetic of Formula Y;
(Ar1)-G-(Ar2)-T-Ewherein;
Ar1 and Ar2 are aryl groups;
G is an atom or group of atoms that links Ar1 and Ar2 through a single C, S, Se, O, or N atom;
T is an atom or group of atoms linking Ar2 to E through 1-4 contiguous atoms or is absent;
E is selected from the group consisting of a functional group or moiety with a pKa≦
7.4, a carboxylic acid moiety, or an atom or group of atoms containing an O or N that binds the thyroid hormone binding pocket of a TRα
or TRβ
;
comprising the step of replacing E with a phosphonic acid or phosphonic acid monoester or prodrug thereof; and
synthesizing a compound of Formula X wherein X is —
P(O)(OH)2 acid or prodrug thereof.
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159. A method of designing a thyromimetic compound with an improved therapeutic index comprising the steps of:
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obtaining a molecular formula for a thyromimetic of Formula Y;
(Ar1)-G-(Ar2)-T-Ewherein;
Ar1 and Ar2 are aryl groups;
G is an atom or group of atoms that links Ar1 and Ar2 through a single C, S, Se, O, or N atom;
T is an atom or group of atoms linking Ar2 to E through 1-4 atoms or is absent;
E is selected from the group consisting of a functional group or moiety with a pKa≦
7.4, a carboxylic acid moiety, or an atom or group of atoms containing an O or N that binds the thyroid hormone binding pocket of a TRα
or TRβ
;
comprising the step of replacing E with a phosphonic acid or phosphonic acid monoester or prodrug thereof; and
synthesizing a compound of Formula X wherein X is —
P(O)(OH)2 acid or prodrug thereof.
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160. A method of increasing the liver specificity of a T3 mimetic having a carboxylic acid moiety comprising the preparation of a compound that is an analog of said T3 mimetic wherein said carboxylic acid moiety is replaced by phosphonic acid or phosphonic acid monoester and prodrugs thereof.
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161. A method of selecting a T3 mimetic having enhanced liver specificity comprising the steps of:
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a) measuring the liver specificity of a T3 mimetic having a carboxylic acid moiety;
b) measuring the liver specificity of a compound that is an analog of said T3 mimetic having a carboxylic acid moiety wherein the carboxylic acid moiety is replaced by a phosphonic acid or phosphonic acid monoester or prodrug thereof; and
comparing the liver specificities of steps a) and b).
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162. A method of screening T3 mimetics comprising the steps of:
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a) measuring a biological effect of T3 mimetic having a carboxylic acid moiety wherein said biological effect is selected from the group consisting of the Ki relative to T3, effects on blood glucose level, effects on serum cholesterol level, effects on fat in the liver, liver specificity, and therapeutic index;
b) measuring the same biological effect measured in a) of a T3 mimetic having a phosphonic acid or phosphonic acid monoester or prodrug moiety thereof; and
c) comparing the results in steps a) and b); and
d) selecting the T3 mimetic of step b) for further scientific evaluation.
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Specification