Novel Phosphorus-Containing Thyromimetics
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Abstract
The present invention relates to compounds of phosphonic acid containing T3 mimetics, 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 syndromex and diabetes.
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Citations
241 Claims
- 1. A compound of Formula I:
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2. A compound of Formula I:
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3-82. -82. (canceled)
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83. A method of preventing or treating a metabolic disease comprising administering to an animal a pharmaceutically effective amount of a phosphonic acid-containing compound, a pharmaceutically acceptable salt thereof, or prodrugs thereof or pharmaceutically acceptable salts of said prodrugs, wherein said phosphonic acid containing compound binds to a thyroid receptor.
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84-99. -99. (canceled)
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100. A method of activating a thyroid receptor in an animal by administering a phosphonic acid-containing-compound wherein said activation results in the 50% or greater increase in the mRNA expression of a gene selected from the group consisting of LDL receptor, ACC, FAS, spot-14, CPT-1, CYP7A, apo AI, and mGPDH.
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101-116. -116. (canceled)
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117. A compound of Formula II:
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118-138. -138. (canceled)
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139. A compound of Formula III:
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140. A compound of Formula III:
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141-226. -226. (canceled)
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227. A phosphonic acid containing thyromimetic compound of Formula X:
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(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, 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 —
P(O)(OH)2 or prodrug thereof;wherein (Ar1)-G-(Ar2)-T-P(O)(OH)2 has a Ki of ≦
150 nM relative to T3;
with the provisos that said —
P(O)(OH)2 containing thryomimetic compound is not;
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228. A method of improving liver versus heart selectivity of a thyromimetic compound of Formula Y:
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(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, 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 —
P(O)(OH)2 or prodrug thereof.
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229. A method of increasing the therapeutic index of a thyromimetic compound of Formula Y:
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(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, 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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230. 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, 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 —
P(O)(OH)2 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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231. 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, 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; and
synthesizing a compound of Formula X wherein X is P(O)(OH)2 acid or prodrug thereof.
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232. A compound of Formula VIII:
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233. 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 P(O)(OH)2 and prodrugs thereof.
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234. 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 P(O)(OH)2 or prodrug thereof; c) comparing the liver specificities of steps a) and b).
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235. 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 prodrug moiety thereof; and c) comparing the results in steps a) and b); d) selecting the T3 mimetic of step b) for further scientific evaluation.
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236-238. -238. (canceled)
Specification