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-11485705-B2
Publication Date
2022-11-01
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 invention relates to indoximod (1-methyl-D-tryptophan) as an IDO pathway inhibitor, including indoximod salts and indoximod prodrugs. The disclosed subject matter provides a prodrug of indoximod comprising ethyl Nα-(L-leucyl)-1-methyl-D-tryptophanate, or a pharmaceutically acceptable salt thereof, and defines prodrugs, salts, substituent groups, stereochemical specification, and acceptable counterions.
The invention further provides indoximod salts and indoximod-prodrug salt forms, including hydrochloride, phosphate, methanesulfonate, hydrogen sulfate, hydrogen phosphate, besylate, glutaminyl prodrug sulfate, and lysyl-derivative sulfate/phosphate. The descriptions include crystalline anhydrous salt forms and analytical characterization selected from 1H NMR, XRPD, DSC, TGA, ELSD, HPLC, and PLM.
The described approach includes pharmaceutical compositions and oral administration of indoximod prodrugs or salts. The stated rationale is that indoximod has non-linear human PK that may limit attainment of immunomodulatory exposure levels after administration, and the disclosure aims to increase indoximod Cmax and exposure after oral administration versus equivalent molar dosing of indoximod free base.
Claims Coverage
The independent claims cover three inventive features: a specific indoximod prodrug, a pharmaceutical composition containing that prodrug or its salt with a pharmaceutically acceptable carrier, and a method of treating cancer by administering that composition to a subject. The claim scope is anchored to ethyl Nα-(L-leucyl)-1-methyl-D-tryptophanate and its pharmaceutically acceptable salts.
Specific indoximod prodrug identity
A prodrug of indoximod comprising ethyl Nα-(L-leucyl)-1-methyl-D-tryptophanate, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with carrier
A pharmaceutical composition of indoximod comprising ethyl Nα-(L-leucyl)-1-methyl-D-tryptophanate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Cancer treatment by administering the composition
A method of treating cancer comprising administering to a subject in need thereof, a therapeutically effective amount of a composition comprising ethyl Nα-(L-leucyl)-1-methyl-D-tryptophanate, or a pharmaceutically acceptable salt thereof.
Permitted pharmaceutically acceptable salt forms
The claims refine the prodrug and/or pharmaceutical composition by specifying pharmaceutically acceptable salts, including phosphate and hydrochloride salts and broader enumerated salt selections.
Cancer treatment indication narrowing
The method claims further narrow the treated cancer to selected cancers including melanoma, colon cancer, lung cancer, or breast cancer, with melanoma singled out in a further dependent claim.
Overall, the claims cover ethyl Nα-(L-leucyl)-1-methyl-D-tryptophanate (indoximod) as a prodrug and as a component of pharmaceutical compositions, together with pharmaceutically acceptable salts. The method claims apply that composition to treating cancer in a subject in need thereof, with dependent claims narrowing salt type and cancer indication.
Stated Advantages
Increases indoximod Cmax and exposure after oral administration versus equivalent molar dosing of indoximod free base.
May limit failure to attain immunomodulatory exposure levels after administration.
Documented Applications
Modulating the IDO pathway.
Treating cancer or tumor-associated immunosuppression via oral administration.
Treating infectious-disease immunosuppression via oral administration, including HIV-1 infection and influenza.
Treating cancer in a subject in need by administering a therapeutically effective amount of a composition comprising ethyl Nα-(L-leucyl)-1-methyl-D-tryptophanate or a pharmaceutically acceptable salt.
Treating selected cancers including melanoma, colon cancer, lung cancer, or breast cancer.
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