Process for producing a hydrate of a hydrochloride salt of 2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl))diacetic acid
Inventors
Ban, Hitoshi • KAMIOKA, Seiji • Sawayama, Yusuke • Li, Chiang Jia
Assignees
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Publication Number
US-11414394-B2
Publication Date
2022-08-16
Expiration Date
Abstract
A process for producing a hydrate of a hydrochloride salt of 2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl))diacetic acid of the formula: wherein the process comprises the following step: recrystallizing the hydrochloride salt of 2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl))diacetic acid, in the presence of hydrochloric acid and a recrystallization solvent; wherein the recrystallization solvent is methanol, ethanol, 2-propanol, diethyl ether, ethyl acetate, benzene, toluene, acetone, dichloromethane, chloroform, hexane, dimethylformamide, acetonitrile, or water; or mixed solvent thereof.
Core Innovation
The invention relates to water-soluble prodrugs of 2-acetylnaphtho[2,3-b]furan-4,9-dione and pharmaceutically acceptable salts, hydrates, and solvates. The prodrugs are intended as anticancer medicaments for therapeutic cancer treatment and prophylactic agent use, and the document defines the prodrug concept around compounds that convert to an active form through non-enzymatic, chemical and/or pH-dependent conversion pathways.
The parent 2-acetylnaphtho[2,3-b]furan-4,9-dione is stated to target cancer stem cells but suffers from poor oral absorption due to high crystallizability. The disclosed formula (1)/(1A) family uses structural variables including A1, A2, B, X/Y/Z/V, and R1/R2/R3/R4/R5/R8, with V defined as —NHR5 or a nitrogen-containing cyclic heterocycle and with additional substitution constraints for the prodrug family.
The disclosure also describes preparation of related compound variants, including generic prodrug intermediates, protected amino intermediates, diacetic acids, carbamate derivatives, and salt and hydrate forms. The synthetic route elements include protection, activation, coupling, deprotection, hydrochloric-acid deprotection from Boc-protected precursors, recrystallization of hydrochloride salts in the presence of hydrochloric acid, and formation of hydrate forms using water or water-containing solvent mixtures.
Claims Coverage
The consolidated claim coverage includes two independent claim themes: a broad compound or pharmaceutically acceptable salt claim, and a process claim for producing a hydrate of a hydrochloride salt of the specified diacetic acid by recrystallization in hydrochloric acid using water or water/selected solvent mixtures. The inventive coverage is centered on these two features, with dependent claims narrowing hydrate form, upstream deprotection, and selected reagent or solvent choices.
Water-soluble anticancer prodrug compound or pharmaceutically acceptable salt
A compound, or a pharmaceutically acceptable salt thereof.
Hydrochloride salt hydrate by recrystallization in hydrochloric acid with water or water-containing solvent mixtures
A process for producing a hydrate of a hydrochloride salt of 2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl)diacetic acid, comprising recrystallizing the hydrochloride salt in the presence of hydrochloric acid and a recrystallization solvent, wherein the recrystallization solvent is water, or a mixture of water and one or more additional solvents selected from acetone, acetonitrile, benzene, chloroform, dichloromethane, diethyl ether, N,N-dimethylformamide, ethanol, ethyl acetate, hexane, isopropanol, methanol, and toluene.
The claim coverage centers on broad compound/salt coverage and a process for producing a hydrate of a hydrochloride salt by recrystallization in hydrochloric acid with water or defined water-containing solvent mixtures, with dependent claims adding hydrate-form and precursor-conversion refinements.
Stated Advantages
The prodrug is water-soluble, enabling oral and intravenous administration.
The parent compound targets cancer stem cells.
The parent compound has poor oral absorption due to high crystallizability, which is addressed by the water-soluble prodrug approach.
Reduces interspecies/individual differences by converting the prodrug to an active form via non-enzymatic, chemical/pH-dependent pathways rather than esterase conversion.
Documented Applications
Therapeutic cancer treatment as an anticancer medicament.
Prophylactic agent use for cancer.
Combination therapy with a second active substance, including chemotherapeutic, hormonal, immunotherapeutic, biological, targeted, or cell-growth-factor related agents.
Cancer treatment areas explicitly listed in the disclosure include acute leukemia, CLL, CML, polycythemia vera, malignant lymphoma, brain tumors, head & neck, esophageal, thyroid, small cell lung, non-small cell lung, breast, gastric, hepatoma, pancreatic, and colon/rectal.
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