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-9850248-B2
Publication Date
2017-12-26
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 immunosuppression associated with an infectious disease.
Core Innovation
The disclosure relates to compounds of a formula, or pharmaceutically acceptable salts thereof, with an imidazo[5,1-a]isoindole core and substituted cyclohexyl or piperidine scaffolds bearing an alcohol motif. The structural definition constrains bond a, n, and substituent groups including R1, R2 as —CH2—RA—, and conditional definitions for RA and Z, with further variables R31, R32, R33, R34, R35, R36, and R10.
The document further describes extensive functional-group variation, including benzoate, acetate, phosphate, carboxamide, phenylcarbamate, succinate-type prodrugs, and related intermediates. The examples include fluoro-substituted, heteroaryl-substituted, and stereochemically defined compounds, together with protected and deprotected alcohol, ethanone, carbamate, amide, oxime, and sulfonamide variants.
The biological portion evaluates human IDO protein expression/purification and enzyme/cell-based assays for IDO inhibition, with activity classification based on IC50-based categorization. The content also includes measurements associated with T-cell proliferation reversal and a pharmacological value table related to IDO inhibition and T-cell proliferation reversal, and the disclosed uses include reversing IDO-mediated immunosuppression and treating conditions benefiting from IDO enzymatic inhibition.
Claims Coverage
The consolidated claim coverage centers on one broad independent claim family that recites a compound or pharmaceutically acceptable salt defined by a complex variable substituent formula. The claim family repeatedly narrows the same framework through bond a, n, m, and p, together with constrained choices for R1, R2/RA, Z, R31, R32, R33, R34, R35, R36, and R10.
Compound formula with conditional bond-dependent substituent definitions
A compound of the formula, or a pharmaceutically acceptable salt thereof, wherein bond a is a single bond or a double bond, n is 0, 1 or 2, and each R1 is independently fluoro, chloro, hydroxy, or methoxy, with R2 defined as —CH2—RA— and Z defined according to the bond a case.
RA functional group options on the R2 linker
RA is selected from —CN, —C(O)R3, —C(O)OR3, —C(O)N(R3)(Rc), —C(ORB)(R3)(Rc), —C(NHRB)(R3)(Rc), or —C(=N—ORc)R3, with RB hydrogen or C1-6 alkyl and RC hydrogen or C1-6 alkyl.
Bond a-dependent Z substituent selection
When bond a is a single bond, Z is —C(R36)2—, —C(=R32)—, —N(R35)—, or —O—; when bond a is a double bond, Z is —C(R36)= or —N(R36)=, with R35 and R36 constrained by the claim.
Restricted variable substituent sets for R32, R31, and R10
R32 includes spiro-(C3-8 cycloalkyl) and spiro-(3-10 membered heterocyclyl) forms and related heteroatom-linked options, R31 is limited to enumerated halogen, cyano, nitro, alkyl, haloalkyl, OR, N(R)2, SR, carbonyl, and sulfonyl-containing groups, and R10 covers alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, and corresponding alkyl-linked forms with optional substitution by listed groups.
Diastereomeric alcohol formation and chiral separation within the compound family
The document describes reduction or formation of diastereomeric alcohols, coupling to sulfonamides, and preparative chiral SFC separation for the described imidazo[5,1-a]isoindole-containing cyclohexyl derivatives.
Prodrug derivatization of a hydroxyethyl core
The document describes preparation of phosphate, acetate, benzoate, carboxamide, phenylcarbamate, and succinate-type prodrugs of a hydroxyethyl core, including prodrug intermediates.
The claim coverage is anchored in a broad compound genus defined by the same variable formula, with repeated structural constraints on bond a, n, RA, Z, and the remaining substituent variables. The disclosed dependent-claim refinements and examples consistently support the same scaffold family, including substituted imidazo[5,1-a]isoindole derivatives, stereoisomeric forms, prodrug variants, and related characterization.
Stated Advantages
Provides activity classification based on IC50-based IDO inhibition measurements and includes evaluation for T-cell proliferation reversal associated pharmacological value.
Reducing tumor growth rates in vivo.
Statistically significant differences in tumor growth curves.
Improved median survival.
High long-term tumor-free survival for compound 1304 (70–80% tumor free after 60 days).
Reversing IDO-mediated immunosuppression.
Enhancing anti-cancer therapy.
Treating tumor-associated or infection-associated immunosuppression, including HIV-1 infection.
Documented Applications
In vivo evaluation of IDO inhibitors for antitumor activity alone and in combination with cyclophosphamide, paclitaxel, doxorubicin, and gemcitabine in syngeneic mouse tumor models including LLC, EMT6, CT26, and MB49.
Treatment of cancers using IDO modulation/IDO inhibition.
Treatment of viral infections including HIV and HIV-1 using IDO modulation/IDO inhibition.
Treatment of IDO-associated diseases using IDO modulation/IDO inhibition.
Combination therapy with standard chemotherapeutics and/or antivirals.
IDO imaging/quantitation using labeled compounds.
Use in enzyme/cell-based assays evaluating IDO inhibition, including activity classification based on IC50-based categorization.
Use in assays evaluating T-cell proliferation reversal.
Use of human IDO protein expression/purification for subsequent enzyme/cell-based IDO inhibition evaluation.
Treating conditions benefiting from IDO enzymatic inhibition.
Reversing IDO-mediated immunosuppression.
Enhancing anti-cancer therapy.
Treating tumor-associated immunosuppression.
Treating infection-associated immunosuppression, including HIV-1 infection.
Interested in licensing this patent?