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Azepine inhibitors of Janus kinases

a technology of janus kinase and azepine, which is applied in the field of compounding, can solve the problems of adversely affecting patient health, poor prognosis, and elevated levels of circulatin cytokines, and achieves the effects of improving patient health, reducing the number of patients, and improving the quality of li

Inactive Publication Date: 2007-06-28
INCYTE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Importantly, activation of STAT signaling, as well as other pathways downstream of JAKs (e.g. Akt), has been correlated with poor prognosis in many cancer types (Bowman, T., et al.
Moreover, elevated levels of circulatin cytokines that signal through JAK / STAT may adversely impact patient health as they are thought to play a causal role in cachexia and / or chronic fatigue.
It has been known that certain therapeutics can cause immune reactions such as skin rash or diarrhea in some patients.
For some patients, these immune reactions may be bothersome, but for others, the immune reactions such as rash or diarrhea may result in inability to continue the treatment.

Method used

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  • Azepine inhibitors of Janus kinases
  • Azepine inhibitors of Janus kinases
  • Azepine inhibitors of Janus kinases

Examples

Experimental program
Comparison scheme
Effect test

preparation of example 1

Intermediate A-1: 2-fluoro-3-iodopyridine

[0206] To a 1 neck-round flask N,N-diisopropylamine (20 mL, 0.14 mol) was dissolved in tetrahydrofuran (50 mL) and was cooled to −78° C. To the resulting mixture, 1.6 M of n-butyllithium in hexanes (86 mL, 0.14 mol) was added and the reaction was stirred at −78° C. for 10 minutes and then warmed to 0° C. and stirred for 15 minutes. 2-fluoropyridine (10 mL, 0.1 mol) was dissolved in 50 mL anhydrous tetrahydrofuran and the resulting mixture was cooled at −78° C. The LDA solution from the first flask was then added. The reaction was stirred at −78° C. for 1.5 hours and then iodine (32 g, 0.13 mol) was added. The mixture was stirred at −78° C. for and additional 1 hour and was then quenched with NH4Cl (aq). The reaction was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (10% EtOAc 90% hexanes) to give 16.3 g of the desired product. 1H NMR (400 MHz...

preparation of example 25

Intermediate B-1: 4-[(vinyloxy)methyl]cyclohexylmethyl methanesulfonate

[0214] 4-[(Vinyloxy)methyl]cyclohexylmethanol (2.0 g, 0.010 mol) was dissolved in chloroform (20 mL), cooled to 0° C., and then methanesulfonyl chloride (0.85 mL, 0.011 mol) and triethylamine (1.5 mL, 0.011 mol) were added. The reaction was stirred at 0° C. for 2 hours. The reaction was extracted with ethyl acetate, and the extracts were washed with water, brine, and then dried over MgSO4 and concentrated. The product was purified via column chromatography on silica gel (40% ethyl acetate, 60% hexanes), to give 1.53 g of the desired product as a 3:1 mixture of the two diastereomers. 1H NMR (400 MHz, CDCl3): δ 6.36-6.41 (m, 1H), 4.04-4.10 (m, 2H), 3.94-3.96 (m, 2H), 3.39-3.43 (m, 2H), 2.92 (s, 3H), 0.90-1.80 (m, 10H) (major diastereomer).

Intermediate B-2: 4-[(vinyloxy)methyl]cyclohexylacetonitrile

[0215] 4-[(Vinyloxy)methyl]cyclohexylmethyl methanesulfonate (1.43 g, 0.00576 mol) was dissolved in dimethyl sulfoxi...

preparation of example 41

Intermediate C-1: 2-chloro-N,N-diethylnicotinamide

[0220] Into a 1-neck round-bottom flask under an atmosphere of nitrogen was dissolved 2-chloronicotinoyl chloride (2.12 g, 0.0120 mol) in methylene chloride (25 mL) and the reaction cooled to 0° C. N-ethylethanamine (2.7 mL, 0.026 mol) was added to the mixture and stirred at 0° C. for 2 hours and then at 20° C. for 16 hours. The reaction was extracted with dichloromethane and the organic extracts were washed with water, brine, dried (MgSO4), and concentrated in vacuo. The crude product was used in the next reaction without further purification. 1H NMR (400 MHz, CDCl3): δ 8.42-8.44 (m, 1H), 7.64-7.65 (m, 1H), 7.29-7.63 (m, 1H), 3.75-3.79 (m, 1H), 3.35-3.40 (m, 1H), 3.13-3.22 (m, 2H), 1.82 (t, 3H), 1.088 (t, 3H). MS: [M+1]=213.

Intermediate C-2: N,N-diethyl-2-[(4-methylpyridin-3-yl)amino]nicotinamide

[0221] Into a 1-neck round-bottom flask was added 4-methylpyridin-3-amine (1.02 g, 0.00940 mol) and 2-chloro-N,N-diethylnicotinamide (2....

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Abstract

The present invention provides compounds that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases including, for example, immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Ser. No. 60 / 719,462, filed Sep. 22, 2005, and U.S. Ser. No. 60 / 810,490, filed Jun. 2, 2006, the disclosures of each of which are incorporated herein by reference in their entireties.FIELD OF THE INVENTION [0002] The present invention relates to compounds that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases including, for example, immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases. BACKGROUND OF THE INVENTION [0003] The immune system responds to injury and threats from pathogens. Cytokines are low-molecular weight polypeptides or glycoproteins that stimulate biological responses in virtually all cell types. For example, cytokines regulate many of the pathways involved in the host inflammatory response to sepsis. Cytokines influence cell differentiation, proliferation and act...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/55C07D487/22
CPCC07D471/14C07D471/22C07D487/14C07D487/22A61P1/04A61P3/10A61P5/14A61P9/10A61P11/00A61P13/12A61P17/00A61P17/02A61P17/04A61P17/06A61P19/02A61P21/04A61P25/00A61P27/02A61P29/00A61P31/12A61P31/14A61P31/18A61P31/20A61P31/22A61P35/00A61P35/02A61P35/04A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00
Inventor ARVANITIS, ARGYRIOSRODGERS, JAMESCOMBS, ANDREWSPARKS, RICHARDROBINSON, DARIUS
Owner INCYTE
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