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N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase

Inactive Publication Date: 2008-09-04
INCYTE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Anatomic separation of mother and fetus and antigenic immaturity of the fetus cannot fully explain fetal allograft survival.
Furthermore, kynurenine metabolites such as 3-hydroxy-kynurenine (3-OH-KYN) and quinolinic acid (QUIN) have toxic effects on brain function.

Method used

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  • N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
  • N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
  • N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase

Examples

Experimental program
Comparison scheme
Effect test

example 1

N-(3-Chloro-4-fluorophenyl)-N′-hydroxy-3-(3-morpholin-1-ylpropoxy)isoxazole-5-carboximidamide

[0206]

Step A: Methyl 3-(3-bromopropoxy)isoxazole-5-carboxylate

[0207]

[0208]A solution of methyl 3-hydroxyisoxazole-5-carboxylate (3.5 g, 24 mmol) in NAN-dimethylformamide (20 mL) was treated with potassium carbonate (6.8 g, 49 mmol) and 1,3-dibromopropane (2.5 mL, 24 mmol) was added and the mixture was stirred at 40° C. for 1 h. The reaction was diluted with water and extracted with ethyl acetate three times. The combined extracts were dried with magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (0-70% ethyl acetate / hexanes) to give the desired product (1.6 g, 25%). MF=C8H11BrNO4; LCMS calculated for C8H11BrNO4 (M+H)+: m / z=264.

Step B: 3-(3-Bromopropoxy)isoxazole-5-carboxylic acid

[0209]

[0210]A solution of methyl 3-(3-bromopropoxy)isoxazole-5-carboxylate (250 mg, 0.93 mmol) in tetrahydrofuran (1.5 mL) was treated with 1 N aqueous sodiu...

example 2

N-(3-Chloro-4-fluorophenyl)-N′-hydroxy-3-(3-pyrrolidin-1-ylpropoxy)isoxazole-5-carboximidamide

[0216]

Step A: N-(3-Chloro-4-fluorophenyl)-3-(3-pyrrolidin-1-ylpropoxy)isoxazole-5-carboxamide

[0217]

[0218]A solution of 3-(3-bromopropoxy)-N-(3-chloro-4-fluorophenyl)isoxazole-5-carboxamide (38 mg, 0.10 mmol), and pyrrolidine (100 μL, 1.20 mmol) in tetrahydrofuran (1.5 mL) was stirred at room temperature for 4 h. The reaction was diluted with methanol and purified by preparative LCMS to give the desired product (34 mg, 92%). MF=C17H20ClFN3O3; LCMS calculated for C17H20ClFN3O3 (M+H)+: m / z=368.

Step B: N-(3-Chloro-4-fluorophenyl)-N′-hydroxy-3-(3-pyrrolidin-1-ylpropoxy)isoxazole-5-carboximidamide

[0219]This material was prepared according to the procedure of Example 1, Step D, using N-(3-chloro-4-fluorophenyl)-3-(3-pyrrolidin-1-ylpropoxy)isoxazole-5-carboxamide as the starting material. (24 mg, 66%). MF=C17H21ClFN4O3; LCMS calculated for C17H21ClFN4O3 (M+H)+: m / z=383.

example 3

N-(3-Chloro-4-fluorophenyl)-N′-hydroxy-3-morpholin-ylisoxazole-5-carboximidamide

[0220]

Step A: 3-Bromo-N-(3-chloro-4-fluorophenyl)isoxazole-5-carboxamide

[0221]

[0222]This material was prepared according to the procedure of Example 1, Step C, using 3-bromoisoxazole-5-carboxylic acid and 3-chloro-4-fluoro aniline as starting materials. MF=C10H5BrClFN2O2; LCMS calculated for C10H5BrClFN2O2 (M+H)+: m / z=319.

Step B: N-(3-Chloro-4-fluorophenyl)-3-morpholin-4-ylisoxazole-5-carboxamide

[0223]

[0224]A solution of 3-bromo-N-(3-chloro-4-fluorophenyl)isoxazole-5-carboxamide (7.5 mg, 0.024 mmol) in morpholine (1.0 mL) was heated at 180° C. in the microwave for 15 minutes. Purification by preparative LCMS (pH 10 buffer) gave the desired product (3.2 mg, 42%). MF=C14H14ClFN3O3; LCMS calculated for C14H14ClFN3O3 (M+H)+: m / z=326.

Step C: N-(3-Chloro-4-fluorophenyl)-N′-hydroxy-3-morpholin-ylisoxazole-5-carboximidamide

[0225]This material was prepared according to the procedure of Example 1, Step D, using N-...

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Abstract

The present invention is directed to N-hydroxyamidino compounds which are modulators of indoleamine 2,3-dioxygenase (IDO), as well as compositions and pharmaceutical methods thereof.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Ser. No. 60 / 845,711, filed Sep. 19, 2006, the disclosure of which is incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention is directed to modulators of indoleamine 2,3-dioxygenase (IDO), as well as compositions and pharmaceutical methods thereof.BACKGROUND OF THE INVENTION[0003]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 cells, a depletion of Trp resulting from IDO activity is a prominent gamma interferon (IFN-γ)-inducible antimicrobial effector mechanism. IFN-γ stimulation induces activation of IDO, which leads to a depletion of Trp, thereby arresting the growth of Trp-depende...

Claims

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Application Information

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IPC IPC(8): A61K31/5377C07D261/12A61K31/42C12N9/99A61P31/12A61P37/00A61P35/00C12N9/04C07D413/04
CPCC07D261/18C07D333/70C07D307/68C07D261/20A61P17/02A61P25/00A61P25/24A61P25/28A61P27/12A61P29/00A61P31/12A61P35/00A61P35/02A61P37/00A61P37/02A61P37/04A61P37/06A61P43/00
Inventor COMBS, ANDREW P.GLASS, BRIAN M.SPARKS, RICHARD B.YUE, EDDY WAI TSUN
Owner INCYTE
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