Method of synthesizing thyroid hormone analogs and polymorphs thereof
AssigneeMadrigal Pharmaceuticals, Inc.
InventorsRebecca Taub, Charles H. Reynolds
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Abstract
The disclosure describes methods of synthesis of pyridazinone compounds as thyroid hormone analogs and their prodrugs. Preferred methods according to the disclosure allow for large-scale preparation of pyridazinone compounds having high purity. In some embodiments, preferred methods according to the disclosure also allow for the preparation of pyridazinone compounds in better yield than previously used methods for preparing such compounds. Also disclosed are morphic forms of a pyridazinone compound. Further disclosed is a method for treating resistance to thyroid hormone in a subject having at least one TRβ mutation.
Claims18
A method for treating a resistance to thyroid hormone (RTH) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (“Compound A”), wherein said subject has at least one TRβ mutation.
A method for treating a resistance to thyroid hormone (RTH) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (IV):
- wherein
- R3 is H or CH2Ra, in which Ra is hydroxyl, O-linked amino acid, —OP(O)(OH)2 or OC(O)—Rb, Rb being lower alkyl, alkoxy, alkyl acid, cycloalkyl, aryl, heteroaryl, or —(CH2)n-heteroaryl and n being 0 or 1;
- R4 is H;
- and
- R5 is CH2COOH, C(O)CO2H, or an ester or amide thereof, or R4 and R5 together are —N═C(Rc)—C(O)—NH—C(O)—;
- in which Rc is H or cyano;
- wherein said subject has at least one TRβ mutation.
Dependencies are inferred from the claim text.