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IDO Inhibitors

a technology of indoleamine and inhibitors, which is applied in the direction of antiinfectives, drug compositions, immunological disorders, etc., can solve the problem that the fetus cannot fully explain the survival of the fetal allogra

Inactive Publication Date: 2013-10-31
NEWLINK GENETICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent describes methods for treating or preventing medical conditions associated with indoleamine 2,3-dioxygenase (IDO), such as immunosuppression, cancer, and infectious diseases, by administering a compound that inhibits the activity of IDO. The compound can be administered alone or in combination with other treatments, such as an anti-cancer agent or an anti-HIV-1 infection treatment. The technical effect of the patent is that it provides a novel therapeutic approach for targeting IDO to improve the efficacy of existing treatments and enhance immune responses against cancer or infectious diseases.

Problems solved by technology

Anatomic separation of mother and fetus and antigenic immaturity of the fetus cannot fully explain fetal allograft survival.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Method A

Syntheses of Dithiocarbamates with Variations in S-Alkyl Groups (Scheme 1)

[0702]

[0703]A solution of tryptamine 1 (1.0 equiv) in anhydrous CH2Cl2 (10 mL) at 0° C. was treated sequentially with triethylamine (1.1 equiv) then carbon disulfide (1.1 equiv) and stirred for 30 min. After this time, alkyl bromide 2 (1.2 equiv unless indicated otherwise) was added and the reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was then poured into 1 M H2SO4 and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. Purification by flash chromatography (silica, EtOAc / hexanes) afforded the desired product. The dithiocarbamate product typically exists as a z 7:3 mixture of tautomers observed by 1H NMR, and are listed with spectral data.

example 2

Phenethyl 2-(1H-indol-3-yl)ethylcarbamodithioate [Compound 00001]

[0704]

[0705]The reaction of 1 with (2-bromoethyl)benzene (1.2 equiv) was performed as described in Method A. Purification by flash chromatography (silica, gradient of 12% EtOAc / Hexanes to 100% EtOAc) afforded product 00001 (0.148 g, 35%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 8.04 (br s, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.32-7.25 (m, 2H), 7.25-7.20 (m, 4H), 7.16-7.13 (m, 1H), 7.07-7.05 (m, 1H), 6.92 (br s, 1H), 4.11-4.06 (m, 2H), 3.48-3.45 (m, 2H), 3.13 (t, J=6.5 Hz, 2H), 2.97-2.94 (m, 2H) and signals due to a minor tautomer (ca. 31%): 3.78-3.74 (m), 3.59-3.55 (m), 3.10-3.08 (m), 3.05-3.01 (m); ESI MS m / z 341 [M+H]+, HPLC (Method 1) >99% (AUC), tR=13.9 min.

example 3

4-Fluorophenethyl 2-(1H-indol-3-yl)ethylcarbamodithioate [Compound 00003]

[0706]

[0707]The reaction of 1 with 4-fluorophenethyl bromide (0.6 equiv) was performed as described in Method A. Purification by flash chromatography (silica, gradient of 12% EtOAc / Hexanes to 100% EtOAc) afforded product 00003 (0.084 g, 31%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 8.04 (br s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.24-7.13 (m, 4H), 7.08-7.04 (m, 1H), 7.00-6.94 (m, 2H), 6.92 (br s, 1H), 4.11-4.07 (m, 2H), 3.46-3.43 (m, 2H), 3.14 (t, J=7.0 Hz, 2H), 2.94-2.91 (m, 2H) and signals due to a minor tautomer (ca. 31%): 3.79-3.75 (m), 3.55-3.52 (m), 3.11-3.09 (m), 3.01-2.98 (m); ESI MS m / z 359 [M+H]+, HPLC (Method 1) 95.3% (AUC), tR=13.7 min.

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Abstract

Presently provided are methods for (a) modulating an activity of indoleamine 2,3-dioxygenase comprising contacting an indoleamine 2,3-dioxygenase with a modulation effective amount of a compound as described in one of the aspects described herein; (b) treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression in a subject in need thereof, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound as described in one of the aspects described herein; (c) treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound as described in one of the aspects described herein; (d) enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound as described in one of the aspects described herein; (e) treating tumor-specific immunosuppression associated with cancer comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound as described in one of the aspects described herein; and (f) treating immunsupression associated with an infectious disease, e.g., HIV-1 infection, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount a compound as described in one of the aspects described herein.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of the filing dates, under 35 USC §119(e), of U.S. Provisional Application Ser. No. 60 / 991,518 filed 30 Nov. 2007; and U.S. Provisional Application Ser. No. 61 / 050,646, filed 6 May 2008, each of which are hereby incorporated by reference in their entirety.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]The present disclosure relates to compounds and methods for inhibition of indoleamine 2,3-dioxygenase; further the disclosure relates to method of treatment of diseases and disorders mediated by indoleamine 2,3-dioxygenase.[0004]2. Summary of the Related Art[0005]Tryptophan (Trp) is an essential amino acid required for the biosynthesis of proteins, niacin and the neurotransmitter 5-hydroxytryptamine (serotonin). The enzyme indoleamine 2,3-dioxygenase (also known as INDO or IDO) catalyzes the first and rate limiting step in the degradation of L-tryptophan to N-formyl-kynurenine. In human ce...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D333/56C07D307/80C07D277/64
CPCC07D333/56C07D277/64C07D307/80A61K31/138A61K31/506A61P1/12A61P1/16A61P15/06A61P19/02A61P25/24A61P25/28A61P29/00A61P31/00A61P31/04A61P31/06A61P31/12A61P31/14A61P31/18A61P33/02A61P35/00A61P35/02A61P37/00A61P37/02A61P37/04A61P43/00C07C259/06C07C311/48C07C327/44C07C327/48C07C333/20C07D209/14C07D209/18C07D213/40C07D215/26C07D253/07C07D261/20C07D263/22C07D277/36C07D279/06C07D307/81C07D333/58C07D333/60C07D335/06C07D401/06C07D405/12C07D409/12C07D417/06C07D417/12Y02A50/30
Inventor MAUTINO, MARIOJAIPURI, FIROZMARCINOWICZ-FLICK, AGNIESZKAKESHARWANI, TANAYWALDO, JESSE
Owner NEWLINK GENETICS
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