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S1p receptor modulating compounds and use thereof

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Title: S1p receptor modulating compounds and use thereof.
Abstract: The present invention relates to amides that have activity as S1P receptor modulating agents and the use of such compounds to treat diseases associated with inappropriate S1P receptor activity. The compounds may be used as immunomodulators, e.g., for treating or preventing diseases such as autoimmune and related immune disorders including systemic lupus erythematosus, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, type I diabetes, uveitis, psoriasis, myasthenia gravis, rheumatoid arthritis, non-glomerular nephrosis, hepatitis, Behçet's disease, glomerulonephritis, chronic thrombocytopenic purpura, hemolytic anemia, hepatitis and Wegner's granuloma; and for treating other conditions. ...


Browse recent Amgen, Inc. patents - Thousand Oaks, CA, US
Inventors: Susana C. Neira, Xiang Yu, Roland Burli, Victor Cee, Brian Lanman
USPTO Applicaton #: #20120088749 - Class: 51421018 (USPTO) - 04/12/12 - Class 514 
Drug, Bio-affecting And Body Treating Compositions > Designated Organic Active Ingredient Containing (doai) >Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai >Hetero Ring Is Four-membered And Includes At Least One Ring Nitrogen >Having -c(=x)-, Wherein X Is Chalcogen, Bonded Directly To The Four-membered Hetero Ring >Additional Hetero Ring Attached Directly Or Indirectly To The Four-membered Hetero Ring By Nonionic Bonding

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The Patent Description & Claims data below is from USPTO Patent Application 20120088749, S1p receptor modulating compounds and use thereof.

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This application claims the benefit of U.S. provisional No. 60/994,812, filed Sep. 20, 2007, the content of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to compounds that have activity as S1P receptor modulating agents and the use of such compounds to treat diseases associated with inappropriate S1P receptor activity.

BACKGROUND OF THE INVENTION

Sphingosine-1-phosphate (S1P) has been demonstrated to induce many cellular effects, including those that result in platelet aggregation, cell proliferation, cell morphology, tumor cell invasion, endothelial cell chemotaxis and endothelial cell in vitro angiogenesis. S1P receptors are therefore good targets for therapeutic applications such as wound healing and tumor growth inhibition. S1P signals cells in part via a set of G protein-coupled receptors named S1P1, S1P2, S1P3, S1P4, and S1P5 (formerly called EDG-1, EDG-5, EDG-3, EDG-6, and EDG-8, respectively). These receptors share 50-55% amino acid and cluster identity with three other receptors (LPA1, LPA2, and LPA3 (formerly EDG-2, EDG-4 and EDG-7)) for the structurally-related lysophosphatidic acid (LPA).

A conformational shift is induced in the G-Protein Coupled Receptor (GPCR) when the ligand binds to that receptor, causing GDP to be replaced by GTP on the α-subunit of the associated G-proteins and subsequent release of the G-proteins into the cytoplasm. The α-subunit then dissociates from the βγ-subunit, and each subunit can then associate with effector proteins, which activate second messengers leading to a cellular response. Eventually the GTP on the G-proteins is hydrolyzed to GDP, and the subunits of the G-proteins re-associate with each other and then with the receptor. Amplification plays a major role in the general GPCR pathway. The binding of one ligand to one receptor leads to the activation of many G-proteins, each capable of associating with many effector proteins, leading to an amplified cellular response.

S1P receptors make good drug targets, because individual receptors are both tissue- and response-specific. Tissue specificity of the S1P receptors is important, because development of an agonist or antagonist selective for one receptor localizes the cellular response to tissues containing that receptor, limiting unwanted side effects. Response specificity of the S1P receptors is also important because it allows for development of agonists or antagonists that initiate or to suppress certain cellular responses without affecting other things. For example, the response specificity of the S1P receptors could allow for an S1P mimetic that initiates platelet aggregation without affecting cell morphology.

S1P is formed as a metabolite of sphingosine in its reaction with sphingosine kinase, and is abundantly stored in platelet aggregates where high levels of sphingosine kinase exist and sphingosine lyase is lacking. S1P is released during platelet aggregation, accumulates in serum and is also found in malignant ascites. S1P biodegradation most likely proceeds via hydrolysis by ectophosphohydrolases, specifically the sphingosine 1-phosphate phosphohydrolases.

SUMMARY

OF THE INVENTION

The present invention relates to the use of new compositions which include S1P modulators, e.g., agonists, partial agonists, inverse agonists and antagonists, and their use in treating, preventing or curing various S1P receptor-related conditions. The invention features compounds which are S1P receptor modulators; in an embodiment, such compounds include those having the formula

and pharmaceutically acceptable salts thereof, wherein R1, Z2, L, B, A, Z1, Z2, Y and X are defined herein.

DETAILED DESCRIPTION

OF THE INVENTION

In one embodiment, the present invention relates to a compound having the formula

or a pharmaceutically-acceptable salt thereof, wherein: A is phenyl or a six-membered heteroaryl containing 1 or 2 N atoms, the phenyl and heteroaryl being substituted by 0, 1, 2 or 3 substituents selected from F, Cl, Br, OC1-4alk, C1-4alk, and C1-4haloalk; B is phenyl or a six-membered heteroaryl containing 1 or 2 N atoms, the phenyl and heteroaryl being substituted by 0, 1, 2 or 3 substituents selected from F, Cl, Br, OC1-4alk, C1-4alk, and C1-4haloalk; L is —C≡C—, —CH2CH2—, —N(Ra)C(═O)— or —C(═O)N(Ra)—; n is 0, 1, 2 or 3; Ra is, independently in each instance; H or C1-6alk; R1 is selected from C1-6alk, OC1-5alk, N(Ra)C1-5alk, N(C1-5alk)C1-5alk, aryl or heteroaryl. X is selected from WC(═O)OR6a, WP(═O)R6bR6c, WS(═O)2OH, WCONHSO3H or 1H-tetrazol-5-yl; wherein W is a direct bond, oxygen or C1-4alk having one or more substituents independently selected from halogen, OH, cyano, NRaRa, arylamino, heteroarylamino, OC1-4alk and CO2H; R6a is hydrogen or C1-4alk; and R6b and R6c are independently hydrogen, OH, C1-4alk or C1-4haloalk; Y is residue of formula (a) wherein the left and right asterisks indicate the point of attachment

wherein Q is selected from a direct bond, C═O, C═S, SO2, C═ONRa or (CR10R11)m; and m is 0, 1, 2 or 3; R7 and R8 are independently selected from hydrogen, halogen, amino, C1-5alkamino, OH, cyano, C1-6alk, C1-6alk(OH), SC1-5alk, OC1-5alk, C1-6haloalk and OC1-5alk; or R7 and R8 may be joined together with the atoms to which they are attached to form a 4- to 7-membered ring, optionally having a heteroatom selected from N, O and S; and R9 is selected from hydrogen, halogen, OH, cyano, C1-6alk, SC1-5alk, OC1-5alk, C1-6haloalk or OC1-5haloalk; R10 and R11 are independently selected from hydrogen, halogen, OH, cyano, C1-6alk, OC1-5alk, SC1-5alk, C1-6haloalk or OC1-5haloalk and Z1 and Z2 are independently selected from O, NR3, S, S(═O), S(═O)2, S(═O)2NR3, (CR4R5)n, C═O, C═S, C═N—R3, or a direct bond, wherein R3 is selected from hydrogen, OH, SO2, C═O, C═S, C═NH, C1-6alk, OC1-5alk, SC1-5alk, C1-6haloalk and OC1-5haloalk, aryl or heteroaryl; or when Z2 is a direct bond, R3 is a C3-C6 ring optionally containing a heteroatom; and R4 and R5 are independently selected from hydrogen, halogen, OH, cyano, C1-6alk, OC1-5alk, SC1-5alk, C1-6haloalk and OC1-5haloalk, aryl and heteroaryl or together form C═O.

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stats Patent Info
Application #
US 20120088749 A1
Publish Date
04/12/2012
Document #
13327951
File Date
12/16/2011
USPTO Class
51421018
Other USPTO Classes
548953, 51421017, 5462681
International Class
/
Drawings
0


Crohn's Disease
Crohn\'s Disease
Hemolytic
Inflammatory Bowel Diseases


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