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Ido inhibitors

A diluent and pharmaceutical technology, applied in the direction of anti-inflammatory agent, antiviral agent, non-central analgesic agent, etc., can solve the problem of anatomical separation of fetal antigen immaturity and so on

Inactive Publication Date: 2010-12-29
NEWLINK GENETICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Maternal-fetal anatomical separation and fetal antigenic immaturity do not fully account for fetal allograft survival

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0834] Method A: Synthesis of allosteric dithiocarbamates with S-alkyl groups (Scheme 1)

[0835] Diagram 1.

[0836]

[0837] at 0 °C in anhydrous CH 2 Cl 2 A solution of tryptamine 1 (1.1 equiv) was treated with triethylamine (1.1 equiv) followed by carbon disulfide (1.1 equiv) in (10 mL) and stirred for 30 minutes. After this time, alkyl bromide 2 (1.2 equiv unless otherwise stated) was added and the reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was then poured into 1M H 2 SO 4 and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, in anhydrous Na 2 SO 4 Dry, then filter and concentrate. Purification by flash chromatography (silica, ethyl acetate / hexanes) afforded the desired product. pass 1H nuclear magnetic resonance spectroscopy observation, dithiocarbamate products generally exist in the form of about 7:3 tautomeric mixture, and listed spectral data.

Embodiment 2

[0839] Phenylethyl 2-(1H-indol-3-yl)ethyldithiocarbamate [Compound 00001]

[0840]

[0841] The reaction of 1 with (2-bromoethyl)benzene (1.2 eq.) was carried out as described in Method A. Purification by flash chromatography (silica, gradient 12% ethyl acetate / hexanes to 100% hexanes) afforded the product 00001 (0.148 g, 35%) as a yellow oil: 1 H nuclear magnetic resonance spectroscopy (500MHz, CDCl 3 ), 8.04(br s, 1H), 7.62(d, J=7.5Hz, 1H), 7.38(d, J=8.0Hz, 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 = 6.5Hz, 2H), 2.97-2.94(m, 2H) and signal due to minor tautomers (about 31%): 3.78-3.74(m), 3.59-3.55(m), 3.10-3.08 (m), 3.05-3.01(m); ESI MSm / z 341[M+H] + , HPLC (method 1)>99% (AUC), t R = 13.9 minutes.

Embodiment 3

[0843] 4-Fluorophenethyl 2-(1H-indol-3-yl)ethyldithiocarbamate [Compound 00003]

[0844]

[0845] Reaction of 1 with 4-fluorophenethyl bromide (0.6 equiv) was carried out as described in Method A. Purification by flash chromatography (silica, gradient 12% ethyl acetate / hexanes to 100% ethyl acetate) afforded the product 00003 (0.084 g, 31%) as a yellow oil: 1 H nuclear magnetic resonance spectroscopy (500MHz, CDCl 3 ), 8.04(br s, 1H), 7.63(d, J=8.0Hz, 1H), 7.39(d, J=8.0Hz, 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=7.0Hz, 2H), 2.94-2.91(m, 2H) and signal due to slight tautomers (about 31%): 3.79-3.75(m), 3.55-3.52(m), 3.11-3.09(m), 3.01-2.98( m); ESI MSm / z 359 [M+H] + , HPLC (method 1) 95.3% (AUC), t R = 13.7 minutes.

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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 immunosuppression associated with an infectious disease, e.g., HIV-I infection, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount a compound as described in one of the aspects described herein.

Description

[0001] Cross References to Related Applications [0002] This application is asserted under 35 USC § 119(e) of U.S. Provisional Application No. 60 / 991,518, filed November 30, 2007, and U.S. Provisional Application No. 61 / 050,646, filed May 6, 2008 Japanese rights and interests; two applications are fully incorporated in the present invention by reference. field of invention [0003] This aspect relates to compounds and methods for inhibiting indoleamine 2,3-dioxygenase; the invention further relates to methods of treating diseases or disorders mediated by indoleamine 2,3-dioxygenase. Background technique [0004] Tryptophan (Trp) is an essential amino acid required for the biosynthesis of proteins, niacin, and the neurotransmitter serotonin (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-kynuric acid step. In human cells, IFN-γ-stimulated induction lea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/506A61K31/00A61P31/00A61P35/00
CPCC07C327/48C07D307/80C07D333/56C07D261/20C07D401/06C07D409/12C07D335/06C07D215/26C07D253/07C07C327/44C07C333/20C07D417/06C07C311/48C07D209/18A61K31/138C07D307/81C07D263/22A61K31/506C07D405/12C07D333/58C07D277/64C07D277/36C07D333/60C07C259/06C07D417/12C07D209/14C07D279/06C07D213/40A61P1/12A61P1/16A61P15/06A61P19/02A61P25/24A61P25/28A61P29/00A61P31/00A61P31/04A61P31/06A61P31/12A61P31/14A61P31/18A61P33/02A61P35/00A61P35/02A61P37/00A61P37/02A61P37/04A61P43/00Y02A50/30
Inventor 马里奥·莫蒂诺菲罗兹·杰普里阿格尼茨卡·马西诺维茨-弗里克塔内伊·克沙瓦尼杰西·瓦尔多史蒂文·J·科利尔
Owner NEWLINK GENETICS
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