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Inhibitors of indoleamine 2,3-dioxygenase (IDO)

A C3-C8, C2-C10 technology, applied in the field of enzyme active compounds, can solve the problem of increased tolerance of the tumor microenvironment

Inactive Publication Date: 2015-12-30
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, overexpression of IDO can lead to increased tolerance in the tumor microenvironment

Method used

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  • Inhibitors of indoleamine 2,3-dioxygenase (IDO)
  • Inhibitors of indoleamine 2,3-dioxygenase (IDO)
  • Inhibitors of indoleamine 2,3-dioxygenase (IDO)

Examples

Experimental program
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preparation example Construction

[0223] The preparation of prodrugs is well known in the art and described, for example, in King, F.D., ed., Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (2 nd edition, reproduced, 2006); Testa, B.etal., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, 3 rd edition, Academic Press, San Diego, CA (2008).

[0224] The present invention is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include atoms with the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 c. Isotopically-labeled compounds of the invention can be prepared generally by conventional techniques known to those skilled in the art or by methods a...

Embodiment 1

[0386] Racemic Example 1. Racemic (1R,2S)-2-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)cyclopropanecarboxylic acid

[0387] To a solution of 1D (140 mg, 0.421 mmol) in THF (4 mL) was added 1-isocyanato-4-methylbenzene (0.079 mL, 0.632 mmol). The resulting solution was stirred at room temperature for 3 h. LC-MS indicated completion. The reaction mixture was concentrated and used in the next step without purification. The crude ester (180 mg, 0.387 mmol) was dissolved in THF (4 mL), and NaOH (1N aq) (1.160 mL, 1.160 mmol) was added. MeOH (1 mL) was then added to dissolve the precipitate and it became a clear yellow solution. After 60 h, LC-MS indicated that the reaction was complete. Most of the MeOH and THF were removed in vacuo and the crude was diluted with 2 mL of water and the pH was adjusted to ~2 using 1N aqueous HCl. The aqueous phase was then extracted with EtOAc (3×10 mL) and the combined organic phases were washed with brine, washed with Na 2 SO 4 Dried a...

Embodiment 2-16

[0425]

[0426] Following the procedure of Method C of Enantiomer 1 of Example 1, using the corresponding isocyanate, Examples 2-16 were prepared.

[0427]

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PUM

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Abstract

There are disclosed compounds that modulate or inhibit the enzymatic activity of indoleamine 2,3-dioxygenase (IDO), pharmaceutical compositions containing said compounds and methods of treating proliferative disorders, such as cancer, viral infections and / or inflammatory disorders utilizing the compounds of the invention.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application 61 / 791,224, filed March 15, 2013, the disclosure of which is hereby incorporated by reference in its entirety. technical field [0003] The present invention generally relates to compounds that modulate or inhibit the enzymatic activity of indoleamine 2,3-dioxygenase (IDO), pharmaceutical compositions containing said compounds and the use of compounds of the present invention in the treatment of proliferative disorders such as cancer, viral infections and and / or methods for autoimmune diseases. Background technique [0004] Tryptophan is an amino acid that is essential for cell proliferation and survival. Indoleamine-2,3-dioxygenase is a heme-containing intracellular enzyme that catalyzes the first and rate-determining step in the degradation of the essential amino acid L-tryptophan to N-formyl-kynurenine. N-formyl-kynurenine is then metabolized throug...

Claims

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Application Information

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IPC IPC(8): C07D261/02C07C233/07C07D239/22C07D213/60
CPCC07C255/44C07C255/57C07D213/84C07C275/42C07D317/66C07C311/51C07D239/42C07D241/42C07D257/04C07D261/08C07C233/55C07D261/14C07C235/38C07D271/12C07D213/56C07B2200/07C07C2601/02C07C2601/08C07C2601/14C07C2602/42A61K31/18A61K31/196A61K31/216A61K31/27A61K31/36A61K31/41A61K31/42A61K31/4245A61K31/44A61K31/498A61K31/505C07D213/75A61P1/04A61P1/18A61P11/00A61P13/08A61P13/12A61P15/00A61P17/00A61P25/00A61P25/24A61P31/12A61P35/00A61P35/02A61P37/02A61P43/00Y02A50/30C07C2602/02C07C2602/08C07C2602/14A61K45/06A61N5/10C07C69/743C07C271/28C07C311/47
Inventor J·A·巴洛格A·黄陈斌陈利冰S·P·塞兹A·C·哈特J·A·马克瓦尔德
Owner BRISTOL MYERS SQUIBB CO
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