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Inhibitors of indoleamine 2,3-dioxygenase for the treatment of cancer

A C3-C8, C2-C10 technology, applied in the field of indoleamine 2,3-dioxygenase inhibitors for the treatment of cancer, can solve problems such as increased tumor microenvironment tolerance

Inactive Publication Date: 2018-05-29
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 for the treatment of cancer
  • Inhibitors of indoleamine 2,3-dioxygenase for the treatment of cancer
  • Inhibitors of indoleamine 2,3-dioxygenase for the treatment of cancer

Examples

Experimental program
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preparation example Construction

[0268] 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 (2nd ed., reprinted 2006); Testa, B. et al., 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, 3rd Edition, Academic Press, San Diego , CA (2008).

[0269] The present invention is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having 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 14c. Isotopically-labeled compounds of the invention can generally be prepared using an appropriate isotopically-labeled reagent in place of an otherwise...

Embodiment 1

[0515] 3-(3-((4-chlorophenyl)amino)-4-(ethyl(4-hydroxy-4-methylcyclohexyl)amino)phenyl)-3-methylbutanoic acid

[0516]

[0517] 1A.8-Methyl-1,4-dioxaspiro[4.5]decane-8-ol

[0518] Cool a stirred solution of 1,4-dioxaspiro[4.5]decane-8-one (5 g, 32.0 mmol) in dry THF (70 mL) to -70 °C and add methyl bromide in ether dropwise over 10 min Magnesium (23.48 mL, 70.4 mmol). The cooling bath was allowed to warm to room temperature and the mixture was stirred overnight. use NH 4 The mixture was quenched with saturated aqueous Cl (75 mL) and extracted with ether (2 x 300 mL). The combined ether extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 1A (yellow liquid, 5.1 g, 29.6 mmol, 92% yield), which was used in the next step without Further purification. 1 H NMR (400MHZ, CDCl 3 )δ3.96-3.90(m, 4H), 1.91-1.84(m, 2H), 1.71-1.65(m, 3H), 1.63-1.57(m, 3H), 1.22(s, 3H).

[0519] 1B. 4-Hydroxy-4-methylcyclohex...

Embodiment 2-4

[0541]

[0542] Examples 2-4 were prepared from 1H diastereomer 2 and the corresponding halide following the procedure described in Synthetic Example 1 .

[0543]

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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 priority to U.S. Provisional Application Serial No. 62 / 142,589, filed April 3, 2015, the entire contents of which are incorporated herein by reference. field of invention [0003] The present invention relates generally 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 Methods of infection and / or autoimmune disease. Background of the invention [0004] Tryptophan is an amino acid essential for cell proliferation and survival. Indoleamine-2,3-dioxygenase is a heme-containing intracellular enzyme that catalyzes the first and rate-limiting step in the degradation of the essential amino acid L-tryptophan to N-formyl-kynurenine . N-formyl-kynurenine is then metabolized through multi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14C07D413/14C07C255/57C07C255/58C07D309/04C07D309/14C07C275/40C07D317/46C07D335/02C07D401/12C07D239/34C07D405/12C07D407/12C07D239/47C07D409/12C07D413/12C07D417/12C07D471/04C07D471/08C07D487/04C07C235/38C07D487/08C07C235/56C07D205/04C07D265/30C07D207/08C07D265/36C07D207/12C07D277/64C07D211/08C07D211/14C07D295/155C07D307/22A61P35/00A61P35/02A61P37/02A61P35/04A61P29/00A61P17/00A61P19/02A61P31/12
CPCC07C229/42C07C235/38C07C235/56C07C255/57C07C255/58C07C275/40C07D205/04C07D207/08C07D211/08C07D211/14C07D239/47C07D265/30C07D265/36C07D277/64C07D295/155C07D307/22C07D309/04C07D309/14C07D335/02C07D401/12C07D405/12C07D405/14C07D407/12C07D409/12C07D413/12C07D417/12C07D471/04C07D487/04C07D487/08A61K31/17A61K31/196A61K31/277A61K31/351A61K31/382A61K31/397A61K31/428A61K31/437A61K31/445A61K31/501A61K31/505A61K31/506A61K31/519A61K31/5375A61K31/5377A61K31/538A61K39/3955A61K39/39558A61K45/06C07D207/12C07D239/34C07D317/46C07D413/14C07D471/08C07D211/10A61P17/00A61P19/02A61P29/00A61P31/12A61P35/00A61P35/02A61P35/04A61P37/02A61P43/00C07C233/81C07C275/42C07C275/30
Inventor J.A.巴罗E.C.彻尔尼郭伟巍A.黄J.A.马克沃尔德S.P.塞茨单伟芳D.K.威廉斯N.穆鲁格桑S.J.纳拉S.罗伊S.桑加维尔R.K.西斯特拉S.彻鲁库S.桑加蒂鲁帕希Y.肯亚博伊纳N.普利查拉
Owner BRISTOL MYERS SQUIBB CO
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