Benzoxazine Derivatives As CRAC Modulators

Benjamin Blass

doi:10.1021/ml400375u

editorial

. 2013 Oct 10;4(11):1020–1021. doi: 10.1021/ml400375u

Benzoxazine Derivatives As CRAC Modulators

Benjamin Blass ^1,^*

PMCID: PMC4027535 PMID: 24900600

Title:	Benzoxazine Derivatives As CRAC Modulators
Patent/Patent Application Number:	WO2013/050270A1	Publication date:	April 11th, 2013
Priority Application:	US 61/543,436	Priority date:	October 5th, 2011
Inventors:	Bhagirath, N.; Brameld, K. A.; Kennedy-Smith, J.
Assignee Company:	F. Hoffmann-La Roche, AG.
Disease Area:	Arthritis, respiratory disease	Biological Target:	Calcium release-activated calcium channel (CRAC)
Summary:	The inflammatory response mediated by interleukin 2 (IL-2) has been linked to a number of important disease states such as rheumatoid arthritis, allergic reactions, and asthma. On-going efforts to identify viable biological targets capable of modulating IL-2 production have included an examination of the calcium channels that regulate calcium influx into T-cell, specifically the calcium release-activated Ca²⁺ channel (CRAC). This channel is a store-operated Ca²⁺ channel present in T-cells, is actived upon antigen binding, and is the primary route of entry for Ca²⁺. The in-flux of Ca²⁺ stimulates T-cell proliferation and IL-2 production and leads to increases in other pro-inflammatory cytokines such as IL-1, IL-6, and TNFα. Given its important role in the regulation of T-cell Ca²⁺ concentration, it has been suggested that compounds capable of blocking CRAC activity would be useful anti-inflammatory agents. The present patent application describes a series of benzoxazine derivatives capable of blocking the CRAC channel and their method of use for the treatment of the inflammatory diseases arthritis, chronic obstructive pulmonary disorder, and bronchospasm.
Important Compound Classes:
Definitions:	R¹ is phenyl, unsubsituted or mono- or bisubstituted independently with halogen.
	R² is phenyl unsubsituted or mono- or bisubstituted independently with lower alkyl, halogen, halo-lower alkyl, alkoxy, unsubstituted five-membered heteroaryl ring, or five-membered heteroaryl ring substituted with lower alkyl;
	-pyridine, unsubsituted or mono- or bisubstituted independently with lower alkyl, halogen, halo-lower alkyl, alkoxy, SO₂CH₂CH₃, unsubstituted five-membered heteroaryl ring, five-membered heteroaryl ring substituted with lower alkyl, unsubstituted six-membered heteroaryl ring, or six-membered heteroaryl ring substituted with an amino moiety;
	or
	-a five-membered herteroaryl ring, unsubsituted or mono- or bisubstituted independently with lower alkyl, halogen, halo-lower alkyl, alkoxy, unsubstituted five-membered heteroaryl ring, five-membered heteroaryl ring substituted with lower alkyl, unsubstituted six-membered heteroaryl ring, or six-membered heteroaryl ring substituted with lower alkyl.
Key Structures:
Recent Review Articles:	Derler I.; Fritsch R.; Schindl R.; Romanin C.. CRAC inhibitors: identification and potential. Expert Opin. Drug Discovery 2008, 3 (7), 787–800.
Biological Assay:	Jurkat IL-2 production assay.
	Human whole blood (HWB) IL-2 production assay.
	³H Thymidine incorporation (MLR) assay.
Biological Data:
Claims:	18 Total claims.
	11 Composition of matter claims.
	7 Method of use claims.