IDO inhibitors
Inventors
Mautino, Mario • Kumar, Sanjeev • Waldo, Jesse • Jaipuri, Firoz • Kesharwani, Tanay • Zhang, Xiaoxia
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10233190-B2
Publication Date
2019-03-19
Expiration Date
Abstract
Presently provided are IDO inhibitors and pharmaceutical compositions thereof, useful for modulating an activity of indoleamine 2,3-dioxygenase; treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression; treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase; enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent; treating tumor-specific immunosuppression associated with cancer; and treating immunosupression associated with an infectious disease.
Core Innovation
The disclosure describes compounds based on an imidazo[5,1-a]isoindole scaffold, defined by Formula II, or pharmaceutically acceptable salts thereof, with variable substituents n, m, p, R1, R3, Z, R31, RC, and R defined through lists of allowed groups. The structures include ethanol-containing motifs and related alcohol, ketone, amide, sulfonamide, carbamate, ester, phosphate/phosphate-like, and carboxylate forms, together with stereodefined variants.
The disclosed examples include specific substituted 5H-imidazo[5,1-a]isoindol-5-yl compounds with piperidine, cyclohexyl, tetrahydro-2H-pyran, azetidine, and other heterocyclic or aryl substituents. The examples also include halogenated and substituted aryl groups, such as fluorophenyl, difluorophenyl, trifluoromethyl phenyl, chloro, nitro, pyridinyl, pyrimidinyl, thiazolyl, furan, imidazolyl, and dimethylfuran variants, as well as protected or derivatized forms such as benzoate, acetate, and tert-butyl carboxylate derivatives.
The partial content further documents characterization and structural assignment of individual scaffold members by 1H NMR, structure drawings, and related analytical data. Some examples describe stereodefined compounds, mixtures of diastereomers, and named members such as tetrahydro-2H-pyran ethanol isomers and cyclohexyl or piperidine-derived analogs.
Claims Coverage
The provided claim coverage centers on a Formula II compound family, or pharmaceutically acceptable salts thereof, with broadly defined substituent classes and dependent refinements. Across the combined inputs, the inventive features are the imidazo[5,1-a]isoindole scaffold, variable substituent definitions, stereochemical configurations, specific tetrahydro-2H-pyran ethanol isomers, and pharmaceutical composition coverage.
Formula II imidazo[5,1-a]isoindole scaffold
A compound of Formula II, or a pharmaceutically acceptable salt thereof, with n being 0 or 1, each R1 independently being halogen, —OR, —N(R)2, or —SR, R3 defined as a single bond, m being 0, 1, or 2, p being 0 or 1, and Z being —O—.
Defined substituent framework for R31, R33, RC, and R
Each R31 is independently selected from halogen, cyano, nitro, C1-6 alkyl, —C1-6 alkyl-R33, C1-6 haloalkyl, —OR, —N(R)2, —SR, —C(O)OR, —C(O)N(R)2, —C(O)R, —S(O)R, —S(O)OR, —S(O)N(R)2, —S(O)2R, —S(O)2OR, —S(O)2N(R)2, —OC(O)R, —OC(O)OR, —OC(O)N(R)2, —N(R)C(O)R, —N(R)C(O)OR, or —N(R)C(O)N(R)2; R33 is —OR, —N(R)2, or —SR; RC is hydrogen or C1-6 alkyl; and each R is independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, phenyl, 5- or 6-membered heteroaryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocyclyl, benzyl, (5- or 6-membered heteroaryl)C1-6 alkyl, C3-8 cycloalkylC1-6 alkyl, C3-8 cycloalkenylC1-6 alkyl, or (3-8 membered heterocyclyl)C1-6 alkyl.
Specific tetrahydro-2H-pyran ethanol isomers
A compound of Formula II is specified as 2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)ethanol or 2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(tetrahydro-2H-pyran-3-yl)ethanol, or a pharmaceutically acceptable salt of either.
Stereochemical configuration at carbon-1 and carbon-3
A stereoisomeric compound is defined by Formula II with stereochemical configuration (R,R) at carbon-1 and carbon-3, and an alternative stereoisomeric configuration (S,R) at carbon-1 and carbon-3.
Pharmaceutical composition with pharmaceutically acceptable diluent, excipient, or carrier
A pharmaceutical composition includes the compound of Formula II together with a pharmaceutically acceptable diluent, excipient, or carrier.
Overall, the claims cover Formula II compounds built on an imidazo[5,1-a]isoindole scaffold with broadly defined substituent classes, discrete parameter choices, specific tetrahydro-2H-pyran ethanol isomer embodiments, explicit stereochemical configurations at carbon-1 and carbon-3, and pharmaceutical composition coverage.
Stated Advantages
Inhibits indoleamine-2,3-dioxygenase (IDO).
Reduces tryptophan degradation, including N-formylkynurenine.
Treats IDO-mediated immunosuppression in cancers and infectious/viral diseases, including HIV.
Enhances anti-cancer therapy.
Tumor growth reduction in vivo antitumor testing.
Improved median survival time in vivo.
Improved overall survival fraction in vivo.
Documented Applications
Treating IDO-mediated immunosuppression in cancers.
Treating infectious/viral diseases, including HIV.
IDO inhibitor use in in vivo antitumor testing, including reported tumor growth reduction and improved median/overall survival in syngeneic C57Bl6 mice and tumor allograft models (LLC, EMT6, CT26, MB49).
Therapeutic use for enhancing anti-cancer therapy by modulating IDO activity.
Connection of the described derivatives to indoleamine-2,3-dioxygenase (IDO) inhibition, including an IDO enzymatic assay using kynurenine with IC50 categorization and an IDO cell-based assay using IDO-293-T-REx, supported by a pharmacology table listing hIDO IC50 categories A–D.
Interested in licensing this patent?