Methods of synthesizing thyroid hormone analogs and polymorphs thereof
Inventors
Hester, II, D. Keith • Duguid, Robert J. • Kelly, Martha J. • Chasnoff, Anna • Dong, Gang • Crow, Edwin L. • Shu, Lianhe • Wang, Ping • Choi, Duk Soon
Assignees
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Publication Number
US-10894050-B2
Publication Date
2021-01-19
Expiration Date
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.
Core Innovation
The invention relates to a process for preparing Compound A, a thyroid-hormone-receptor-related compound, through intermediates that include 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one and a morphic form of Compound A. The process includes contacting R1MgX or R1Li with a compound of Formula (I) to form a compound of Formula (II), where R1 is isopropyl or isopropenyl and X is halo, and converting the resulting Formula (II) intermediate to a compound of Formula (III) under conditions that depend on whether R1 is isopropenyl or isopropyl.
The process further includes, when present, removing the amine protecting group R2 of the compound of Formula (III) to form 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one. This intermediate is then converted to 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). The process also forms a morphic form of Compound A (Form I), characterized by an X-ray powder diffraction pattern with peaks at about 10.5, 18.7, 22.9, 23.6, and 24.7 degrees 2θ.
The document describes a therapeutic method for treating resistance to thyroid hormone in a subject having at least one TRβ mutation by administering a Formula (IV) compound, including Compound A. Responsiveness determination is also referenced by detecting TR mutations. The background context is resistance to thyroid hormone (RTH) in subjects with at least one TRβ mutation.
Claims Coverage
The independent claim set includes a compound claim and a process claim. Across the independent claims, the inventive features are structural specificity of the compounds, an XRPD-defined morphic form, and a defined intermediate-to-product conversion sequence using Formula (I), R1MgX or R1Li, and Formula (II)/Formula (III) intermediates.
Compound selection and salt inclusion
A compound selected from the provided compound set and a salt thereof.
XRPD-defined morphic form of Compound A
Forming a morphic form of Compound A (Form I) characterized by an X-ray powder diffraction pattern that includes peaks at about 10.5, 18.7, 22.9, 23.6, and 24.7 degrees 2θ.
Formula (I) to Formula (II) intermediate formation using R1MgX or R1Li
Contacting R1MgX or R1Li with a compound of Formula (I) to form a compound of Formula (II), wherein R1 is isopropyl or isopropenyl, X is halo and R2 is H or an amine protecting group.
Formula (II) to Formula (III) intermediate conversion dependent on R1 and optional R2 deprotection to Int. 7
Converting the compound of Formula (II) to a compound of Formula (III), in the presence of a base when R1 is isopropenyl or in the presence of an oxidizing agent when R2 is isopropyl, and when present removing the amine protecting group R2 of Formula (III) to form 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one.
Conversion to Compound A
Converting 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one to 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).
The independent claim set focuses on a selected compound and salt thereof, and a process that builds Compound A from Formula (I) via R1MgX/R1Li chemistry to Formula (II) and Formula (III), includes optional R2 deprotection to form Int. 7, converts Int. 7 to Compound A, and forms Form I defined by a specific XRPD peak set.
Stated Advantages
Improved regioselectivity.
Higher purity.
Avoiding isolation of a biaryl ether intermediate with prolonged filtration in prior routes.
Higher yield versus prior art.
Easier processing.
Reduced regioisomer.
Reduced heavy metal; heavy-metal free.
Documented Applications
Treatment methods for resistance to thyroid hormone (RTH) in subjects with at least one TRβ mutation, including responsiveness determination/diagnostic methods referenced in the provided content.
Therapeutic method for treating resistance to thyroid hormone (RTH) in a subject having at least one TRβ mutation using a Formula (IV) compound including Compound A.
Responsiveness determination by detecting TR mutations.
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