Salts and prodrugs of 1-methyl-D-tryptophan
Inventors
Mautino, Mario • Kumar, Sanjeev • Jaipuri, Firoz • Waldo, Jesse • POTTURI, Hima • Zhuang, Hong
Assignees
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Publication Number
US-10207990-B2
Publication Date
2019-02-19
Expiration Date
Abstract
Presently provided are indoximod prodrug and salt compounds and pharmaceutical compositions comprising salts and prodrugs of indoximod, that produce enhanced plasma concentration and exposure to indoximod compared to direct administration of indoximod, in patients in need of treatment of immunosuppression mediated by the indoleamine-2,3-dioxygenase pathway, such as patients with cancer or chronic infectious diseases.
Core Innovation
The disclosure provides crystalline forms of a salt of 1-methyl-D-tryptophan, including pharmaceutically acceptable salt forms and HCl salts. It identifies 1-methyl-D-tryptophan HCl salt Form 1 and includes anhydrous and substantially pure crystalline forms, together with selected salt counterions.
The disclosure also relates to indoximod as an indoleamine-2,3-dioxygenase (IDO) pathway inhibitor and provides indoximod salts and indoximod prodrugs, including Formula 2 compounds with defined substituents, stereochemistry, and optional acid counterions. It further includes explicit exclusions and support for pharmaceutically acceptable salts and defined salt stoichiometries.
The disclosed prodrugs and crystalline salt forms are used for modulating the IDO pathway and are positioned in cancer and tumor-specific immunosuppression contexts, with further references to infectious disease contexts. The disclosure also relates to pharmaceutical compositions comprising the indoximod salts and indoximod prodrugs, including therapeutic use for cancer types such as melanoma, colon cancer, lung cancer, and breast cancer.
Claims Coverage
The independent claims cover crystalline salt forms of 1-methyl-D-tryptophan, Formula 2 indoximod prodrugs for cancer treatment, and an HCl salt of 1-methyl-D-tryptophan. In total, the claims emphasize crystalline form, salt identity, structural constraints, and selected cancer indications.
Crystalline form of a salt of 1-methyl-D-tryptophan
A crystalline form of a salt of 1-methyl-D-tryptophan, including anhydrous and substantially pure crystalline forms and 1-methyl-D-tryptophan HCl salt Form 1.
Cancer treatment by administering constrained Formula 2 compound
A method of treating cancer in a subject by administering a therapeutically effective amount of a compound of Formula 2 or a pharmaceutically acceptable salt thereof, with defined substituent and stereochemistry constraints and an explicit proviso excluding specified compounds; the cancer is selected from melanoma, colon cancer, lung cancer, or breast cancer.
HCl salt of 1-methyl-D-tryptophan
An HCl salt of 1-methyl-D-tryptophan.
Overall, the claims cover crystalline salt-form material for 1-methyl-D-tryptophan, including HCl salt Form 1 and substantially pure, anhydrous forms, and cancer-treatment methods that administer either a constrained Formula 2 compound or the claimed crystalline form, with cancer indications limited to selected cancer types.
Stated Advantages
Elevates indoximod plasma Cmax and AUC versus equivalent molar free-base indoximod.
Documented Applications
Treatment of cancer in a subject, where cancer is selected from melanoma, colon cancer, lung cancer, or breast cancer.
Indoximod use as an IDO pathway inhibitor for immunosuppression mediated by the indoleamine-2,3-dioxygenase pathway.
Modulating the indoleamine-2,3-dioxygenase (IDO) pathway in cancer and tumor-specific immunosuppression contexts.
Oral administration and therapeutic application for cancer types including melanoma, colon cancer, lung cancer, and breast cancer.
Further references to infectious disease contexts.
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