WO2008079382A1 - Composés d'agonistes et d'antagonistes des récepteurs de sphingosine-1-phosphate - Google Patents

Composés d'agonistes et d'antagonistes des récepteurs de sphingosine-1-phosphate Download PDF

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Publication number
WO2008079382A1
WO2008079382A1 PCT/US2007/026263 US2007026263W WO2008079382A1 WO 2008079382 A1 WO2008079382 A1 WO 2008079382A1 US 2007026263 W US2007026263 W US 2007026263W WO 2008079382 A1 WO2008079382 A1 WO 2008079382A1
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WIPO (PCT)
Prior art keywords
alkyl
substituted
optionally substituted
aryl
alkoxy
Prior art date
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PCT/US2007/026263
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English (en)
Inventor
Grier A. Wallace
Eric C. Breinlinger
Kevin P. Cusack
Shannon R. Fix-Stenzel
Thomas D. Gordon
Adrian D. Hobson
Martin E. Hayes
Graham K. Ansell
Pintipa Grongsaard
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Abbott Laboratories
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=39562856&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2008079382(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to CA002672727A priority Critical patent/CA2672727A1/fr
Priority to JP2009542960A priority patent/JP2010513532A/ja
Priority to MX2009006751A priority patent/MX2009006751A/es
Priority to AU2007338700A priority patent/AU2007338700A1/en
Priority to EP07863237A priority patent/EP2120575A4/fr
Priority to BRPI0720478-7A priority patent/BRPI0720478A2/pt
Publication of WO2008079382A1 publication Critical patent/WO2008079382A1/fr
Priority to EC2009009435A priority patent/ECSP099435A/es
Priority to NO20092376A priority patent/NO20092376L/no

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    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3826—Acyclic unsaturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07F9/653—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
    • C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • Sphingosine-1 -phosphate is part of the sphingomyelin biosynthetic pathway and is known to affect multiple biological processes. SlP is formed through phosphorylation of sphingosine by sphingosine kinases (SKl and SK2) and it is degraded through cleavage by sphingosine lyase to form palmitaldehyde and phosphoethanolamine or through dephosphorylation by phospholipid phosphatases. It is present at high levels ( ⁇ 500 nM) in serum, and it is found in most tissues.
  • GPCR G protein-coupled receptor
  • SlP evokes many responses from cells and tissues.
  • SlP has been shown to be an agonist at all five GPCRs, SlP 1 (Edg-1), SlP 2 (Edg-5), SlP 3 (Edg-3), SlP 4 (Edg-6) and SlP 5 (Edg-8).
  • the action of SlP at the SlP receptors has been linked to resistance to apoptosis, changes in cellular morphology, cell migration, growth, differentiation, cell division, angiogenesis and modulation of the immune system via alterations of lymphocyte trafficking. Therefore, SlP receptors are targets for therapy of, for example, neoplastic diseases, autoimmune disorders and tissue rejection in transplantation.
  • GPCRs are excellent drug targets with numerous examples of marketed drugs across multiple disease areas.
  • GPCRs are cell surface receptors that bind hormones on the extracellular surface of the cell and transduce a signal across the cellular membrane to the inside of the cell. The internal signal is amplified through interaction with G proteins which in turn interact with various second messenger pathways. This transduction pathway is manifested in downstream cellular responses that include cytoskeletal changes, cell motility, proliferation, apoptosis, secretion and regulation of protein expression, to name a few.
  • SIP receptors make good drug targets because individual receptors are expressed in different tissues and signal through different pathways, making the individual receptors both tissue and response specific. Tissue specificity of the SIP receptors is desirable 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 SIP receptors is also of importance because it allows for the development of agonists or antagonists that initiate or suppress certain cellular responses without affecting other responses. For example, the response specificity of the SIP receptors could allow for an SlP mimetic that initiates platelet aggregation without affecting cell morphology.
  • SIP receptors The physiologic implications of stimulating individual SIP receptors are largely unknown due in part to a lack of receptor type selective ligands. Isolation and characterization of SIP analogs that have potent agonist or antagonist activity for SlP receptors have been limited.
  • SlP for example is widely expressed, and the knockout causes embryonic lethality due to large vessel rupture.
  • Adoptive cell transfer experiments using lymphocytes from SDPi knockout mice have shown that SlPj deficient lymphocytes sequester to secondary lymph organs.
  • the present invention provides compounds of Formula I
  • D is H, N(R 5 ) 2 or OR 6 ;
  • X is CH, C(CH 3 ) or N;
  • Y is CH 2 , O, S or NR 3 ; wherein R 3 is hydrogen, or straight or branched (C r Ci 0 ) alkyl;
  • X is CH or N
  • Y is CH 2 , NH, N(CH 3 ), S or O.
  • A is H, -C(O)-OCH 3 , -C(O)-NR 6 , CN, C(O)-NHCH 3 , COOR 6 , -R 4 -C00H, or optionally substituted azetidinyl, wherein R 4 is straight or branched (C r C 2 o) alkylene, straight or branched (C 1 -C 20 ) alkenylene, straight or branched (C 1 -C 20 ) alkynylene;
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, halo, (Ci-Ci 0 ) alkyl, (Ci-Ci 0 ) alkoxy, (C 3 -C 20 ) cycloalkyl substituted alkyl, (C 3 -Ci 0 ) cycloalkyl substituted alkoxy, (C 2 -Ci 0 ) alkenyl, aryl substituted (C 2 -Ci 0 ) alkenyl, (C 2 -C] 0 ) alkynyl, aryl substituted (C 2 -Ci 0 ) alkynyl, aryl, aryl substituted (C r Ci 0 ) alkyl, heteroaryl substituted (Ci-Ci 0 ) alkyl, aryl substituted (C 1 -C 10 ) alkoxy, heteroaryl substituted (C r Cio) alkoxy, (Ci-Ci 0 ) al
  • X is CH
  • Y is CH 2 or O;
  • A is -C(O)-OCH 3 , -COOH, -R 4 -C00H, -C(O)-NHCH 3 , or optionally substituted azetidinyl;
  • R 4 is straight or branched (Ci-Ci 0 ) alkylene, straight or branched (Ci-Ci 0 ) alkenylene, or straight or branched (Ci-Ci 0 ) alkynylene;
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, halo, (Ci-Ci 0 ) alkyl, (Ci-Ci 0 ) alkoxy, (C 3 -Ci 0 ) cycloalkyl substituted alkyl, (C 3 -Ci 0 ) cycloalkyl substituted alkoxy,
  • the invention provides compounds according to any of the foregoing embodiments wherein Y is CH 2 ;
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, (C 1 -C 10 ) alkyl, (C 2 -C 10 ) alkenyl, (C 2 -C 10 ) alkynyl and aryl substituted (C 1 -C 10 ) alkyl; wherein such R 1 and R 2 groups may be optionally substituted with (C 1 -C 10 ) alkyl, halo, hydroxy, (C 1 -C 10 ) alkoxy, or CN; wherein one or more of the carbon atoms in the R 1 or R 2 groups can be independently replaced with non-peroxide oxygen; wherein one of R 1 and R 2 is other than hydrogen.
  • X is CH; Y is CH 2 ;
  • A is COOH
  • R 1 is (Ci-C 10 )alkyl, (C 2 -C 10 )alkenyl or (C 2 -C 10 )alkynyl; R 2 is H; and m is 1.
  • Y is CH 2 , O, S or NR 3 ; wherein R 3 is hydrogen, or (CrCi 0 ) alkyl;
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, halo, straight or branched (C 1 -C 10 ) alkyl, (C r Ci 0 ) alkoxy, (C 3 -Ci 0 ) cycloalkyl substituted alkyl, (C 3 -C 10 ) cycloalkyl substituted alkoxy, (C 2 -C 10 ) alkenyl, aryl substituted (C 2 -C 10 ) alkenyl, (C 2 -Ci 0 ) alkynyl, aryl substituted (C 2 -C 10 ) alkynyl, aryl, aryl substituted alkyl, heteroaryl substituted (C r C 10 )alkyl, aryl substituted alkoxy, heteroaryl substituted alkoxy, (C 1 -C 10 )alkyl substituted aryl, arylalkyl, aryl substituted arylalkyl, aryl substitute
  • R 6 is independently selected from H or optionally substituted (C r C 2 )alkyl
  • R 7 is independently selected from H or optionally substituted (Q-C 2 )alkyl; and u is 1 or 2.
  • X is CH or N
  • Y is CH 2 , O, S or NR 3 ; wherein R 3 is hydrogen, or (C 1 -C 20 ) alkyl;
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, halo, (C r C 20 ) alkyl, (Ci-C 20 ) alkoxy, (C 3 -C 20 ) cycloalkyl substituted alkyl, (C 3 -C 20 ) cycloalkyl substituted alkoxy, (C 2 -C 20 ) alkenyl, aryl substituted (C 2 -C 20 ) alkenyl, (C 2 -C 20 ) alkynyl, aryl substituted (C 2 -C 20 ) alkynyl, aryl, aryl substituted alkyl, heteroaryl substituted alkyl, aryl substituted alkoxy, heteroaryl substituted alkoxy, alkyl substituted aryl, arylalkyl and aryl substituted arylalkyl; wherein such R 2 groups may be optionally substituted with (C r C 20 ) alkyl, halo, hydroxy,
  • Y is CH 2 ;
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, halo, straight or branched (Ci-Ci 0 ) alkyl, aryl substituted (Ci-Ci 0 ) alkyl, heteroaryl substituted alkyl, aryl substituted alkoxy, heteroaryl substituted alkoxy, (Ci-Cio)alkyl substituted aryl, arylalkyl, aryl substituted arylalkyl, arylalkyl substituted arylalkyl, CN and -O-indolizinyl; wherein such R 1 and R 2 groups may be optionally substituted with one or more substitutents independently selected from (Ci-Ci 0 ) alkyl, halo and (Ci-Ci 0 ) alkoxy; wherein one or more of the carbon atoms in the R 1 or R 2 groups can be independently replaced with non-peroxide oxygen; wherein one of R 1 and R 2 is other than hydrogen; and
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, optionally substituted (C r Ci 0 ) alkyl; wherein one or more of the carbon atoms in the R 1 or R 2 groups can be independently replaced with non-peroxide oxygen; wherein one of R 1 and R 2 is other than hydrogen;; m is 1; and u is l.
  • the invention provides compounds of embodiments one, seven, eight, nine and ten wherein the compound is
  • D is H, N(R 5 ) 2 , or OR 6 ;
  • X is CH, C(CH 3 ) or N;
  • Y is CH 2 , O, S or NR 3 ; wherein R 3 is hydrogen, or straight or branched (Ci-Cio) alkyl;
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, CF 3 , halo, (Ci- C 20 ) alkyl, (Ci-C 20 ) alkoxy, (C 3 -C 20 ) cycloalkyl substituted alkyl, (C 3 -C 20 ) cycloalkyl substituted alkoxy, (C 2 -C 20 ) alkenyl, aryl substituted (C 2 -C 20 ) alkenyl, (C 2 -C 2 o) alkynyl, aryl substituted (C 2 - C 20 ) alkynyl, aryl, aryl substituted alkyl, heteroaryl substituted alkyl, aryl substituted alkoxy, heteroaryl substituted alkoxy, alkyl substituted aryl, arylalkyl, aryl substituted arylalkyl, arylalkyl substituted arylalkyl, CN and -O-indolizin
  • X is CH, C(CH 3 ) or N
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, CF 3 , halo, (C 1 - C 20 ) alkyl, (C 1 -C 20 ) alkoxy, (C 3 -C 20 ) cycloalkyl substituted alkyl, (C 3 -C 20 ) cycloalkyl substituted alkoxy, (C 2 -C 20 ) alkenyl, aryl substituted (C 2 -C 20 ) alkenyl, (C 2 -C 20 ) alkynyl, aryl substituted (C 2 -
  • R 1 and R 2 groups may be optionally substituted with one or more substitutents independently selected from (Ci-C 20 ) alkyl, CF 3 , halo, hydroxy, (Ci-C 20 ) alkoxy, OCF 3 , and CN; wherein one or more of the carbon atoms in the R 1 or R 2 groups can be independently replaced with non-peroxide oxygen, sulfur or NR 8 ; wherein R 8 is hydrogen or (Ci-C 20 ) alkyl group; wherein one of R 1 and R 2 is other than hydrogen; and wherein the al
  • the invention provides a method of claim 14 wherein the disorder is rheumatoid arthritis, lupus, Crohn's disease, asthma, diabetes, pain or psoriasis.
  • D is H, N(R 5 ) 2 , or OR 6 ;
  • X is CH, C(CH 3 ) or N;
  • Y is CH 2 , O, S or NR 3 ; wherein R 3 is hydrogen, or straight or branched (Ci-Ci 0 ) alkyl;
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, CF 3 , halo, (Q- C 20 ) alkyl, (C, -C 20 ) alkoxy, (C 3 -C 20 ) cycloalkyl substituted alkyl, (C 3 -C 20 ) cycloalkyl substituted alkoxy, (C 2 -C 20 ) alkenyl, aryl substituted (C 2 -C 20 ) alkenyl, (C 2 -C 20 ) alkynyl, aryl substituted (C 2 - C 20 ) alkynyl, aryl, aryl substituted alkyl, heteroaryl substituted alkyl, aryl substituted alkoxy, heteroaryl substituted alkoxy, alkyl substituted aryl, arylalkyl, aryl substituted arylalkyl, arylalkyl substituted arylalkyl, CN and -O-indoliziny
  • the invention provides a method of treating multiple sclerosis comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of any of the foregoing embodiments or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof.
  • D is H, N(R 5 ) 2 , or OR 6 ;
  • X is CH, C(CH 3 ) or N
  • Y is CH 2 , O, S or NR 3 ; wherein R 3 is hydrogen, or straight or branched (Ci-Ci 0 ) alkyl; A is H, hydroxy, -CH 2 OH, -CH(OH)CH 3 , -C(O)-OCH 3 , -C(OH)(CH 3 ) 2 , -0(CH 2 ) t -C00H,-
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, CF 3 , halo, (C r C 20 ) alkyl, (C]-C 20 ) alkoxy, (C 3 -C 20 ) cycloalkyl substituted alkyl, (C 3 -C 20 ) cycloalkyl substituted alkoxy, (C 2 -C 2 o) alkenyl, aryl substituted (C 2 -C 20 ) alkenyl, (C 2 -C 2O ) alkynyl, aryl substituted (C 2 - C 20 ) alkynyl, aryl, aryl substituted alkyl, heteroaryl substituted alkyl, aryl substituted alkoxy, heteroaryl substituted alkoxy, alkyl substituted aryl, arylalkyl, aryl substituted arylalkyl, arylalkyl substituted arylalkyl, CN and -O-indoli
  • the invention provides the packaged pharmaceutical according to embodiment eighteen wherein the compound or compounds are present in a therapeutically effective amount.
  • the invention provides a compound of Formula 2
  • the invention provides a compound of Formula 5
  • the invention provides a compound of Formula 10
  • the invention provides a compound of Formula 12
  • R 1 or R 2 are independently fluorine or chlorine or fluoro- or chloro- substituted alkyl.
  • Z is hydroxy or -OPO 3 H 2 .
  • R 1 is hydrogen and R 2 is alkyl, akenyl, or alkynyl having 5, 6, 7, 8, or 9 carbon atoms.
  • R 1 is hydrogen and R 2 is heptyl, octyl, nonyl, -O-heptyl,
  • R 1 is hydrogen and R 2 is -(CH 2 ) n -OCH 3 , -(CH 2 ) n -OCF 3 , -O-(CH 2 ) n -OCH 3 , or -O-(CH 2 ) n -OCF 3 , where n is an integer from 1-20, preferably 5, 6, 7, 8, or 9.
  • the R 2 group may be an ortho, meta or para substituent on the phenyl ring, preferably para.
  • the R 1 group may be an ortho, meta or para substituent on the phenyl ring, preferably meta.
  • the invention provides a pharmaceutical composition comprising one or more compounds according to Formula I, or pharmaceutically acceptable salts, solvates, hydrates, metabolites, prodrugs or stereoisomers thereof, and a pharmaceutically acceptable diluent or carrier.
  • the invention provides a pharmaceutical composition wherein the compound or compounds are present in a therapeutically effective amount.
  • the invention provides a pharmaceutical composition wherein the compound or compounds are present in a prophylactically effective amount.
  • the invention provides a packaged pharmaceutical comprising one or more compounds according to Formula I or pharmaceutically acceptable salts, solvates, hydrates, metabolites, prodrugs or stereoisomers thereof and instructions for use.
  • the invention provides a packaged pharmaceutical wherein the compound or compounds are present in a therapeutically effective amount.
  • the invention provides a packaged pharmaceutical wherein the compound or compounds are present in a prophylactically effective amount.
  • the present invention provides novel compounds of Formula I:
  • X is CH or N
  • Y is CH 2 , O, S or NR 3 ; wherein R 3 is hydrogen, or (C 1 -C 10 ) alkyl; Z is hydroxy, phosphate, phosphonate, or ⁇ -substituted phosphonate;
  • R 1 is selected from the group consisting of hydrogen, halo, (Ci-C 20 ) alkyl, (C 1 -C 20 ) alkyl substituted with halo, hydroxy, (Ci-C 20 ) alkoxy, or CN; and
  • R 2 is selected from the group consisting of hydrogen, halo, (C r C 20 ) alkyl, (Ci-C 20 ) alkoxy, (C 3 -C 20 ) cycloalkyl substituted alkyl, (C 3 -C 20 ) cycloalkyl substituted alkoxy, (C 2 -C 20 ) alkenyl, aryl substituted (C 2 -C 20 ) alkenyl, (C 2 -C 20 ) alkynyl, aryl substituted (C 2 -C 20 ) alkynyl, aryl, aryl substituted alkyl, heteroaryl substituted alkyl, aryl substituted alkoxy, heteroaryl substituted alkoxy, alkyl substituted aryl, arylalkyl and aryl substituted arylalkyl; wherein such R 2 groups may be optionally substituted with (Ci-C 20 ) alkyl, halo, hydroxy, (C r
  • Exemplary compounds of Formula I include: (77?,3/?)-l-Amino-3-(4-oct-l-ynyl-phenyl)-cyclopentanecarboxylic acid; (77?,3S)-l-Amino-3-(4-non-l-ynyl-phenyl)-cyclopentanecarboxyIic acid (77?,3S)-l-Arnino-3-(4-nonyl-phenyl)-cyclopentanecarboxylic acid; (77?, 3S)-I -Amino-3-(4-dec-l-ynyl-phenyl)-cyclopentanecarboxylic acid; (77?,55)-l-Amino-3-(4-decyl-phenyl)-cyclopentanecarboxylic acid (77?,35)-l-Amino-3-[4-(7-methoxy-hept-l-ynyl)-
  • a “therapeutically effective amount” is an amount of a compound of Formula I or a combination of two or more such compounds, which inhibits, totally or partially, the progression of the condition or alleviates, at least partially, one or more symptoms of the condition.
  • a therapeutically effective amount can also be an amount which is prophylactically effective. The amount which is therapeutically effective will depend upon the patient's size and gender, the condition to be treated, the severity of the condition and the result sought. For a given patient, a therapeutically effective amount can be determined by methods known to those of skill in the art.
  • Physiologically acceptable salts or “pharmaceutically acceptable salts” refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid or organic acids such as sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, L-aspartic acid, L-mandelic, L-succinic acid, benzoic acid, salicylic acid, lactic acid, tartaric acid (e.g. (+) or (-)-tartaric acid or mixtures thereof), amino acids (e.g. (+) or (-)-amino acids or mixtures thereof), and the like.
  • These salts can be prepared by methods known to those skilled in the art.
  • Certain compounds of Formula I which have acidic substituents may exist as salts with pharmaceutically acceptable bases.
  • the present invention includes such salts.
  • Examples of such salts include sodium salts, potassium salts, lysine salts and arginine salts. These salts may be prepared by methods known to those skilled in the art.
  • Certain compounds of Formula I and their salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof.
  • Certain compounds of Formula I and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.
  • Certain compounds of Formula I may contain one or more chiral centers, and exist in different optically active forms. When compounds of Formula I contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures.
  • the enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a further step may be used to liberate the desired enantiomeric form.
  • specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
  • a compound of Formula I contains more than one chiral center, it may exist in diastereoisomeric forms.
  • the diastereoisomeric compounds may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual stereoismers may be separated as described above.
  • the present invention includes each diastereoisomer of compounds of Formula I and mixtures thereof.
  • Certain compounds of Formula I may exist in different tautomeric forms or as different geometric isomers, and the present invention includes each tautomer and/or geometric isomer of compounds of Formula I and mixtures thereof.
  • Certain compounds of Formula I may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
  • the present invention includes each conformational isomer of compounds of Formula I and mixtures thereof.
  • Certain compounds of Formula I may exist in zwitterionic form and the present invention includes each zwitterionic form of compounds of Formula I and mixtures thereof.
  • pro-drug refers to an agent which is converted into the parent drug in vivo by some physiological chemical process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form).
  • Pro-drugs are often useful because, in some situations, they may be easier to administer than the active metabolite. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • the prodrug may also have improved solubility in pharmacological compositions over the active metabolite.
  • pro-drug a compound of the present invention wherein it is administered as an ester (the "pro-drug") to facilitate transmittal across a cell membrane where water solubility is not beneficial, but then it is metabolically hydrolyzed to the carboxylic acid once inside the cell where water solubility is beneficial
  • Pro-drugs have many useful properties. For example, a pro-drug may be more water soluble than the ultimate drug, thereby facilitating oral administration of the drug. A pro-drug may also have a higher level of oral bioavailability than the ultimate drug. After administration, the prodrug is enzymatically or chemically cleaved to deliver the ultimate drug in the blood or tissue.
  • Exemplary pro-drugs upon cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the compounds of this invention include but are not limited to carboxylic acid substituents (e.g., -(CH 2 )C(O)OH or a moiety that contains a carboxylic acid) wherein the free hydrogen is replaced by (Ci-C 4 ) alkyl, (C 2 -Ci 2 ) alkanoyloxymethyl, (C 4 -C 9 ) 1- (alkanoyloxy)ethyl, l-methyl-l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, l-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- l-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbon
  • exemplary pro-drugs release an alcohol of Formula I wherein the free hydrogen of the hydroxy substituent (e.g., Z contains hydroxy) is replaced by phosphate (PO 4 ), (Ci- C 6 )alkanoyloxymethyl, l-((C r C 6 )alkanoyloxy)ethyl, l-methyl-l-((Ci-C 6 )alkanoyloxy)ethyl, (C r C 6 )alkoxycarbonyloxy-methyl, N-(Ci-C 6 )alkoxycarbonylamino-methyl, succinoyl, (Ci-C 6 )alkanoyl, ⁇ -amino(Ci-C 4 )alkanoyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl wherein said ⁇ - aminoacyl moieties are independently any of the naturally occurring L-amino acids found in proteins, -
  • heterocyclic or “heterocyclyl”, as used herein, include non-aromatic ring systems, including, but not limited to, monocyclic, bicyclic and tricyclic rings, which can be completely saturated or which can contain one or more units of unsaturation (for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system) and have 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur.
  • heterocyclic rings azepines, azetidinyl, morpholinyl, oxopiperidinyl, oxopyrrolidinesyl, piperazinyl, piperidinyl, pyrrolidinyl, quinicludinyl, thiomorpholinyl, tetrahydropyranyl and tetrahydrofuranyl.
  • heteroaryl as used herein, include aromatic ring systems, including, but not limited to, monocyclic, bicyclic and tricyclic rings, and have 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur.
  • azaindole benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, furans, imidazoles, imidazopyridine, indole, indolinyl, indazoles, isoindolinyl, isoxazoles, isothiazoles, oxadiazoles, oxazoles, purine, pyrans, pyrazines, pyrazoles, pyridines, pyrimidines, pyrroles, pyrrolo[2,3- djpyrimidine, pyrazolo[3,4-d]pyrimidine), quinolines, quinazolines, triazoles, thiazoles, thiophenyl, tetrahydroindole, tetrazol
  • substituted heterocyclic or heterocyclyl or “substituted heteroaryl”
  • substituted heterocyclic or heterocyclyl or “substituted heteroaryl”
  • the heterocyclic group is substituted with one or more substituents that can be made by one of ordinary skill in the art and results in a molecule that is an agonist or antagonist of the sphingosine receptor family.
  • preferred substituents for the heterocycle of this invention are each independently selected from the optionally substituted group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylheterocycloalkoxy, alkyl, alkylcarbonyl, alkylester, alkyl-O-C(O)-, alkyl-heterocyclyl, alkyl-cycloalkyl, alkyl-nitrile, alkynyl, amido groups, amino, aminoalkyl, aminocarbonyl, carbonitrile, carbonylalkoxy, carboxamido, -CF 3 , -CN, -C(O)OH, -C(O)H, -C(O)-C(CH 3 ) 3 , -OH, -C(O)O-alkyl, -C(O)O
  • Z 105 for each occurrence is independently a covalent bond, alkyl, alkenyl or alkynyl; and Z 200 for each occurrence is independently selected from an optionally substituted group selected from the group consisting of alkyl, alkenyl, alkynyl, phenyl, alkyl-phenyl, alkenyl-phenyl or alkynyl-phenyl; E is a direct bond, O, S, S(O), S(O) 2 , or NR f , wherein R f is H or alkyl and R 0 and R 6 are independently H, alkyl, alkanoyl or SO 2 -aIkyl; or Ra, R e and the nitrogen atom to which they are attached together to form a five- or six-membered heterocyclic ring.
  • heterocycloalkyl is a heterocyclic group that is linked to a compound by an aliphatic group having from one to eight carbon atoms.
  • a preferred heterocycloalkyl group is a morpholinomethyl group.
  • aliphatic or “an aliphatic group” or notations such as “(Ci-C 20 )” include straight chained or branched hydrocarbons which are completely saturated or which contain one or more units of unsaturation, and, thus, includes alkyl, alkenyl, alkynyl and hydrocarbons comprising a mixture of single, double and triple bonds. When the group is a C 0 it means that the moiety is not present or in other words, it is a bond.
  • alkyl means C]-C 20 and includes straight chained or branched hydrocarbons, which are completely saturated.
  • alkyls are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc. up to twenty carbon atoms, and isomers thereof.
  • alkenyl and alkynyl means C 2 -C 20 and includes straight chained or branched hydrocarbons which contain one or more units of unsaturation, one or more double bonds for alkenyl and one or more triple bonds for alkynyl.
  • aromatic groups include aromatic carbocyclic ring systems (e.g., phenyl and cyclopentyldienyl) and fused polycyclic aromatic ring systems (e.g., naphthyl, biphenylenyl and 1,2,3,4-tetrahydronaphthyl).
  • cycloalkyl means C 3 -C 2O monocyclic or multicyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbons that is completely saturated or has one or more unsaturated bonds but does not amount to an aromatic group.
  • Preferred examples of a cycloalkyl group are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.
  • aryl substituted alkyl or "aryl substituted alkenyl” means moieties such as methylphenyl, ethylphenyl, methylnaphthyl, ethylnapthyl, ethylenylphenyl ethylenylnaphthyl and so on wherein the alkyl portion of the moiety ranges from 1 to 20 carbons and the alkenyl portion of the moiety ranges from 2 to 20 carbons.
  • heteroaryl substituted alkyl means moieties such as methylpyridinyl, ethylpyridinyl and so on wherein the alkyl portion of the moiety ranges from 1 to 20 carbons and the heteroaryl can be any heteroaryl.
  • many moieties or substituents are termed as being either "substituted" or
  • alkenyl groups alkoxy group (which itself can be substituted, such as -0-(Ci- C 6 )alkyl-OR, -O-(Ci-C 6 )alky 1-N(R) 2 , and -OCF 3 ), alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylpiperidinyl-alkoxy, alkyl groups (which itself can also be substituted, such as -Q- C 6 -alkyl-OR, -C 1 -Q-alky 1-N(R) 2 , and -CF 3 ), alkylamino, alkylcarbonyl, alkylester, alkylnitrile, alkylsulfonyl, amino, aminoalkoxy, -CF 3 , -COH, -COOH, -CN, cycloalkyl,
  • the compounds according to the invention may be prepared following synthesis schemes set forth in detail in the Examples below. Methods of Use
  • the present invention provides compounds described by general Formula I which are effective as antagonists or agonists of the G protein-coupled SlP receptor family. These compounds reduce the number of circulating and infiltrating T- and B-lymphocytes, affording a beneficial immunosuppressive effect.
  • the present invention also provides compounds that exhibit activity within the SlP receptor family.
  • the invention provides a method for modulating receptors of the SlP family in a human subject suffering from a disorder in which modulation of SlP activity is beneficial, comprising administering to the human subject a compound of Formula I such that modulation of SlP activity in the human subject is triggered and treatment is achieved.
  • the invention provides a method of modulating sphingosine-1- phosphate receptor 1 (SlPi) activity comprising contacting a cell with one or more compounds of Formula I.
  • a compound of Formula I or a salt thereof or pharmaceutical compositions containing a therapeutically effective amount thereof is useful in the treatment of a disorder selected from the group comprising CNS system disorders, arthritis, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, and septic arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis scleroderma, graft versus host disease, organ transplant rejection (including but not limited to bone marrow and solid organ rejection), acute or chronic immune disease associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki's disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatos
  • such compounds may be useful in the treatment of disorders such as, edema, ascites, effusions, and exudates, including for example macular edema, cerebral edema, acute lung injury, adult respiratory distress syndrome (ARDS), proliferative disorders such as restenosis, fibrotic disorders such as hepatic cirrhosis and atherosclerosis, mesangial cell proliferative disorders such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, and glomerulopathies, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, ischemia/reperfusion injury, peptic ulcer Helicobacter related diseases, virally-induced angiogenic disorders, Crow-Fukase syndrome (POEMS), preeclampsia, menometrorrhagia, cat scratch fever, rubeosis, neovascular glaucoma and
  • these compounds can be used as active agents against solid tumors, malignant ascites, von Hippel Lindau disease, hematopoietic cancers and hyperproliferative disorders such as thyroid hyperplasia (especially Grave's disease), and cysts (such as hypervascularity of ovarian stroma characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome) and polycystic kidney disease since such diseases require a proliferation of blood vessel cells for growth and/or metastasis.
  • thyroid hyperplasia especially Grave's disease
  • cysts such as hypervascularity of ovarian stroma characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome) and polycystic kidney disease since such diseases require a proliferation of blood vessel cells for growth and/or metastasis.
  • Compounds of Formula I of the invention can be used alone or in combination with another therapeutic agent to treat such diseases.
  • an additional agent e.g., a therapeutic agent
  • the additional agent can be a therapeutic agent art-recognized as being useful to treat the disease or condition being treated by the compound of the present invention.
  • the additional agent also can be an agent that imparts a beneficial attribute to the therapeutic composition e.g., an agent that affects the viscosity of the composition.
  • the combinations which are to be included within this invention are those combinations useful for their intended purpose.
  • the agents set forth below are illustrative for purposes and not intended to be limited.
  • the combinations, which are part of this invention can be the compounds of the present invention and at least one additional agent selected from the lists below.
  • the combination can also include more than one additional agent, e.g., two or three additional agents if the combination is such that the formed composition can perform its intended function.
  • Preferred combinations are non-steroidal anti-inflammatory drug(s) also referred to as NSAIDS which include drugs like ibuprofen.
  • Other preferred combinations are corticosteroids including prednisolone; the well known side-effects of steroid use can be reduced or even eliminated by tapering the steroid dose required when treating patients in combination with the SlP receptor agonists or antagonists of this invention.
  • Non-limiting examples of therapeutic agents for rheumatoid arthritis with which a compound of Formula I of the invention can be combined include the following: cytokine suppressive anti-inflammatory drug(s) (CSAIDs); antibodies to or antagonists of other human cytokines or growth factors, for example, TNF, LT, IL-I, IL-2, IL-3, IL- 4, IL-5, IL-6, DL-7, IL-8, IL-12, IL-15, IL-16, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF, and PDGF.
  • CSAIDs cytokine suppressive anti-inflammatory drug(s)
  • S/T kinase inhibitors of the invention can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligands including CD154 (gp39 or CD40L).
  • cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligands including CD154 (gp39 or CD40L).
  • Preferred combinations of therapeutic agents may interfere at different points in the autoimmune and subsequent inflammatory cascade; preferred examples include TNF antagonists like chimeric, humanized or human TNF antibodies, HUMIRATM, (U.S. Patent No. US 6,090,382), CA2 (REMICADETM), CDP 571, and soluble p55 or p75 TNF receptors, derivatives, thereof, (p75TNFRlgG (ENBRELTM) or p55TNFRlgG (Lenercept), and also TNF ⁇ converting enzyme (TACE) inhibitors; similarly IL-I inhibitors (Interleukin-1 -converting enzyme inhibitors, DL-IRA etc.) may be effective for the same reason.
  • TNF antagonists like chimeric, humanized or human TNF antibodies, HUMIRATM, (U.S. Patent No. US 6,090,382), CA2 (REMICADETM), CDP 571, and soluble p55 or p75 TNF receptors, derivatives, thereof, (p75TNFRlg
  • Yet other preferred combinations are the other key players of the autoimmune response which may act parallel to, dependent on or in concert with IL-18 function; especially preferred are EL-12 antagonists including IL-12 antibodies or soluble IL-12 receptors, or IL-12 binding proteins. It has been shown that IL-12 and IL-18 have overlapping but distinct functions and a combination of antagonists to both may be most effective. Yet another preferred combination are non-depleting anti-CD4 inhibitors. Yet other preferred combinations include antagonists of the co-stimulatory pathway CD80 (B7.1) or CD86 (B7.2) including antibodies, soluble receptors or antagonistic ligands.
  • a compound of Formula I of the invention may also be combined with agents, such as methotrexate, 6-MP, azathioprine sulphasalazine, mesalazine, olsalazine chloroquinine/ hydroxychloroquine, pencillamine, aurothiomalate (intramuscular and oral), azathioprine, cochicine, corticosteroids (oral, inhaled and local injection), beta-2 adrenoreceptor agonists (salbutamol, terbutaline, salmeteral), xanthines (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSADDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase
  • IL-l ⁇ converting enzyme inhibitors T-cell signalling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors and the derivatives p75TNFRIgG (EnbrelTM and p55TNFRIgG (Lenercept)), sDL-lRI, sIL-lRII, sIL-6R), antiinflammatory cytokines (e.g.
  • IL-4, IL-10, IL-I l, IL-13 and TGF ⁇ celecoxib, folic acid, hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, naproxen, valdecoxib, sulfasalazine, methylprednisolone, meloxicam, methylprednisolone acetate, gold sodium thiomalate, aspirin, triamcinolone acetonide, propoxyphene napsylate/apap, folate, nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone HCl, hydrocodone bitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra, tramadol HCl, salsalate, sulinda
  • Non-limiting examples of therapeutic agents for inflammatory bowel disease with which a compound of Formula I of the invention can be combined include the following: budenoside; epidermal growth factor; corticosteroids; cyclosporin, sulfasalazine; aminosalicylates; 6- mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide; antioxidants; thromboxane inhibitors; IL-I receptor antagonists; anti-EL-l ⁇ monoclonal antibodies; anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors; pyridinyl-imidazole compounds; antibodies to or antagonists of other human cytokines or growth factors, for example,
  • TNF antagonists for example, anti-TNF antibodies, HUMIRATM ,U.S. Patent No. US 6,090,382;, CA2 (REMICADETM), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBRELTM) and p55TNFRIgG (LenerceptTM)) inhibitors and PDE4 inhibitors.
  • a compound of Formula I can be combined with corticosteroids, for example, budenoside and dexamethasone; sulfasalazine, 5-aminosalicylic acid; olsalazine; and agents which interfere with synthesis or action of proinflammatory cytokines such as EL-I, for example, EL-l ⁇ converting enzyme inhibitors and EL-lra; T cell signaling inhibitors, for example, tyrosine kinase inhibitors 6-mercaptopurines; EL-I l; mesalamine; prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolone sodium succinate; diphenoxylate/atrop sulfate; loperamide hydrochloride; methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water; hydrocodone bitartrate/apap; tetracycline hydrochlor
  • Non-limiting examples of therapeutic agents for multiple sclerosis with which a compound of Formula I can be combined include the following: corticosteroids; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; methotrexate; 4- aminopyridine; tizanidine; interferon- ⁇ la (Avonex®; Biogen); interferon- ⁇ lb (Betaseron®; Chiron/Berlex); interferon ⁇ -n3) (Interferon Sciences/Fujimoto), interferon- ⁇ (Alfa Wassermann/J&J), interferon ⁇ IA-IF (Serono/Inhale Therapeutics), Peginterferon ⁇ 2b (Enzon/Schering-Plough), Copolymer 1 (Cop-1; Copaxone®; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; intravenous immunoglobulin; clabribine; antibodies to or antagonists of
  • a compound of Formula I can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD 19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands.
  • a compound of Formula I may also be combined with agents such as methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which interfere with signalling by proinflammatory cytokines such as TNF ⁇ or DL-I (e.g.
  • KAK, NIK, IKK, p38 or MAP kinase inhibitors KAK, NIK, IKK, p38 or MAP kinase inhibitors
  • DL-l ⁇ converting enzyme inhibitors TACE inhibitors
  • T-cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6- mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g., soluble p55 or p75 TNF receptors, sIL-lRI, sIL-lRII, sIL-6R) and antiinflammatory cytokines (e.g. DL-4, DL-IO, IL-13 and TGF ⁇ ).
  • soluble cytokine receptors e.g., soluble p55 or p75 TNF receptors, sIL-lRI, sIL-lRII
  • Preferred examples of therapeutic agents for multiple sclerosis in which a compound of Formula I can be combined to include interferon- ⁇ , for example, EFN ⁇ la and DFN ⁇ lb; Copaxone, corticosteroids, caspase inhibitors, for example inhibitors of caspase-1, EL-I inhibitors, TNF inhibitors, and antibodies to CD40 ligand and CD80.
  • a compound of Formula I may also be combined with agents, such as alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol, a-immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulated mitoxantrone), THCCBD (cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone allotrap 1258 (RDP-1258), sTNF-Rl, talampanel, teriflunomide, TGF-beta2, tiplimotide, VLA-4 antagonists (for example,
  • I of the invention can be combined include the following: aspirin, nitroglycerin, isosorbide mononitrate, metoprolol succinate, atenolol, metoprolol tartrate, amlodipine besylate, diltiazem hydrochloride, isosorbide dinitrate, clopidogrel bisulfate, nifedipine, atorvastatin calcium, potassium chloride, furosemide, simvastatin, verapamil HCl, digoxin, propranolol hydrochloride, carvedilol, lisinopril, spironolactone, hydrochlorothiazide, enalapril maleate, nadolol, ramipril, enoxaparin sodium, heparin sodium, valsartan, sotalol hydrochloride, fenofibrate, ezetimibe, bumetanide, losartan potassium,
  • Non-limiting examples of therapeutic agents for ankylosing spondylitis with which a compound of Formula I can be combined include the following: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine, minocyclin, prednisone, etanercept, and infliximab.
  • Non-limiting examples of therapeutic agents for asthma with which a compound of Formula I include the following: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine, minocyclin, prednisone, eta
  • I can be combined include the following: albuterol, salmeterol/fluticasone, montelukast sodium, fluticasone propionate, budesonide, prednisone, salmeterol xinafoate, levalbuterol HCl, albuterol sulfate/ipratropium, prednisolone sodium phosphate, triamcinolone acetonide, beclomethasone dipropionate, ipratropium bromide, azithromycin, pirbuterol acetate, prednisolone, theophylline anhydrous, methylprednisolone sodium succinate, clarithromycin, zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillin trihydrate, flunisolide, allergy injection, cromolyn sodium, fexofenadine hydrochloride, flunisolide/menthol, amoxicillin/clavulanate, levofloxacin
  • I can be combined include the following: albuterol sulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone, albuterol, salmeterol xinafoate, fluticasone propionate, prednisone, theophylline anhydrous, methylprednisolone sodium succinate, montelukast sodium, budesonide, formoterol fumarate, triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate, levalbuterol HCl, flunisolide, ceftriaxone sodium, amoxicillin trihydrate, gatifloxacin, zafirlukast, amoxicillin/clavulanate, flunisolide/menthol, chlorpheniramine/hydrocodone, metaproterenol sulfate, methylprednisolone, mom
  • Non-limiting examples of therapeutic agents for HCV with which a compound of Formula I can be combined include the following: Interferon- ⁇ -2a, Interferon- ⁇ -2b, Interferon- ⁇ conl, Interferon- ⁇ -nl, pegylated interferon- ⁇ -2a, pegylated interferon- ⁇ -2b, ribavirin, peginterferon alfa- 2b + ribavirin, ursodeoxycholic acid, glycyrrhizic acid, thymalfasin, Maxamine, VX-497 and any compounds that are used to treat HCV through intervention with the following targets: HCV polymerase, HCV protease, HCV helicase, and HCV IRES (internal ribosome entry site).
  • Non-limiting examples of therapeutic agents for Idiopathic Pulmonary Fibrosis with which a compound of Formula I can be combined include the following: prednisone, azathioprine, albuterol, colchicine, albuterol sulfate, digoxin, gamma interferon, methylprednisolone sod succ, lorazepam, furosemide, lisinopril, nitroglycerin, spironolactone, cyclophosphamide, ipratropium bromide, actinomycin d, alteplase, fluticasone propionate, levofloxacin, metaproterenol sulfate, morphine sulfate, oxycodone HCl, potassium chloride, triamcinolone acetonide, tacrolimus anhydrous, calcium, interferon- ⁇ , methotrexate, mycophenolate mofetil and interferon-gamma-l ⁇ .
  • Non-limiting examples of therapeutic agents for myocardial infarction with which a compound of Formula I can be combined include the following: aspirin, nitroglycerin, metoprolol tartrate, enoxaparin sodium, heparin sodium, clopidogrel bisulfate, carvedilol, atenolol, morphine sulfate, metoprolol succinate, warfarin sodium, lisinopril, isosorbide mononitrate, digoxin, furosemide, simvastatin, ramipril, tenecteplase, enalapril maleate, torsemide, retavase, losartan potassium, quinapril HCl/mag carb, bumetanide, alteplase, enalaprilat, amiodarone hydrochloride, tirofiban HCl m-hydrate, diltiazem hydrochloride, captopril,
  • Non-limiting examples of therapeutic agents for psoriasis with which a compound of Formula I can be combined include the following: calcipotriene, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, methotrexate, fluocinonide, betamethasone diprop augmented, fluocinolone acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole, pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobetasol propionate/emoll, fluticasone propionate, azithromycin, hydrocortisone, moisturizing formula, folic acid, desonide, pimecrolimus, coal tar, diflorasone diacetate, etanercept folate,
  • Non-limiting examples of therapeutic agents for psoriatic arthritis with which a compound of Formula I can be combined include the following: methotrexate, etanercept, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, betamethasone diprop augmented, infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac sodium/misoprostol, fluocinonide, glucos
  • Formula I can be combined include the following: sirolimus, paclitaxel, everolimus, tacrolimus, ABT-578, and acetaminophen.
  • Non-limiting examples of therapeutic agents for sciatica with which a compound of Formula I can be combined include the following: hydrocodone bitartrate/apap, rofecoxib, cyclobenzaprine HCl, methylprednisolone, naproxen, ibuprofen, oxycodone HCl/acetaminophen, celecoxib, valdecoxib, methylprednisolone acetate, prednisone, codeine phosphate/apap, tramadol hcl/acetaminophen, metaxalone, meloxicam, methocarbamol, lidocaine hydrochloride, diclofenac sodium, gabapentin, dexamethasone, carisoprodol, ketorolac tromethamine, indomethacin, acetaminophen, diazepam, nabumetone, oxycodone HCl, tizanidine HC
  • Preferred examples of therapeutic agents for SLE (Lupus) with which a compound of Formula I can be combined include the following: NSAEDS, for example, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin; COX2 inhibitors, for example, celecoxib, rofecoxib, valdecoxib; anti-malarials, for example, hydroxychloroquine; steroids, for example, prednisone, prednisolone, budenoside, dexamethasone; cytotoxics, for example, azathioprine, cyclophosphamide, mycophenolate mofetil, methotrexate; inhibitors of PDE4 or purine synthesis inhibitor, for example Cellcept®.
  • NSAEDS for example, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin
  • COX2 inhibitors for example, celecoxib,
  • a compound of Formula I may also be combined with agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran® and agents which interfere with synthesis, production or action of proinflammatory cytokines such as IL-I, for example, caspase inhibitors like IL-l ⁇ converting enzyme inhibitors and IL-lra.
  • agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran® and agents which interfere with synthesis, production or action of proinflammatory cytokines such as IL-I, for example, caspase inhibitors like IL-l ⁇ converting enzyme inhibitors and IL-lra.
  • a compound of Formula I may also be used with T cell signaling inhibitors, for example, tyrosine kinase inhibitors; or molecules that target T cell activation molecules, for example, CTLA-4-IgG or anti-B7 family antibodies, anti-PD- 1
  • a compound of Formula I can be combined with IL-I l or anti-cytokine antibodies, for example, fonotolizumab (anti-EFNg antibody), or anti-receptor receptor antibodies, for example, anti-IL-6 receptor antibody and antibodies to B-cell surface molecules.
  • a compound of Formula I may also be used with LJP 394 (abetimus), agents that deplete or inactivate B-cells, for example, Rituximab (anti-CD20 antibody), lymphostat-B (anti-BlyS antibody), TNF antagonists, for example, anti-TNF antibodies, HUMIRATM (U.S. Patent No. US 6,090,382;), CA2 (REMICADETM), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBRELTM) and p55TNFRIgG (LENERCEPTTM).
  • the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
  • the compounds of this invention can be administered in combination with another therapeutic agent that is known to treat a disease or condition described herein.
  • additional pharmaceutical agents that inhibit or prevent the production of VEGF or angiopoietins, attenuate intracellular responses to VEGF or angiopoietins, block intracellular signal transduction, inhibit vascular hyperpermeability, reduce inflammation, or inhibit or prevent the formation of edema or neovascularization.
  • the compounds of the invention can be administered prior to, subsequent to or simultaneously with the additional pharmaceutical agent, whichever course of administration is appropriate.
  • the additional pharmaceutical agents include, but are not limited to, anti-edemic steroids, NSAIDS, ras inhibitors, anti-TNF agents, anti-ILl agents, antihistamines, PAF- antagonists, COX-I inhibitors, COX-2 inhibitors, NO synthase inhibitors, Akt/PTB inhibitors, IGF- IR inhibitors, PKC inhibitors, PB kinase inhibitors, calcineurin inhibitors and immunosuppressants.
  • the compounds of the invention and the additional pharmaceutical agents act either additively or synergistically.
  • the administration of such a combination of substances that inhibit angiogenesis, vascular hyperpermeability and/or inhibit the formation of edema can provide greater relief from the deletrious effects of a hyperproliferative disorder, angiogenesis, vascular hyperpermeability or edema than the administration of either substance alone.
  • combinations with antiproliferative or cytotoxic chemotherapies or radiation are included in the scope of the present invention.
  • One or more compounds of the invention can be administered to a human patient by themselves or in pharmaceutical compositions where they are mixed with biologically suitable carriers or excipient(s) at doses to treat or ameliorate a disease or condition as described herein. Mixtures of these compounds can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions.
  • a therapeutically effective dose refers to that amount of the compound or compounds sufficient to result in the prevention or attenuation of a disease or condition as described herein.
  • Techniques for formulation and administration of the compounds of the instant application may be found in references well known to one of ordinary skill in the art, such as "Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, latest edition. Pharmaceutical Compositions and Modes of Administration
  • Suitable routes of administration may, for example, include oral, eyedrop, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
  • compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee- making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • compositions for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoro- methane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoro- methane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds can be formulated for parenteral administration by injection, e.g. bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly or by intramuscular injection).
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • An example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the cosolvent system may be the VPD co-solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 400, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD:5W) consists of VPD diluted 1: 1 with a 5% dextrose in water solution.
  • This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • identity of the cosolvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
  • other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethysulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art.
  • Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • the pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • salts may be provided as salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms.
  • compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated. Determination of the effective amounts is well within the capability of those skilled in the art. Dosage
  • the therapeutically effective dose can be estimated initially from cellular assays.
  • a dose can be formulated in cellular and animal models to achieve a circulating concentration range that includes the EC 50 as determined in cellular assays (i.e., the concentration of the test compound which achieves a half- maximal inhibition of a given receptor activity).
  • the concentration of the test compound which achieves a half- maximal inhibition of a given receptor activity i.e., the concentration of the test compound which achieves a half- maximal inhibition of a given receptor activity.
  • Such information can be used to more accurately determine useful doses in humans.
  • advangtageous compounds for systemic administration effectively modulate receptors of the SlP family in intact cells at levels that are safely achievable in plasma.
  • a therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms in a patient.
  • Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) and the ED 50 (effective dose for 50% maximal response).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between MTD and ED 50 .
  • Compounds which exhibit high therapeutic indices are preferred.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See, e.g., Fingl et al, 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1, p.l).
  • the administration of an acute bolus or an infusion approaching the MTD may be advantageous to obtain a rapid response.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to modulate receptors of the SlP family, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data; e.g. the concentration necessary to achieve 50-90% inhibition of binding of the natural ligand using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
  • Dosage intervals can also be determined using the MEC value.
  • Compounds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and more preferably between 50-90% until the desired amelioration of symptoms is achieved.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • compositions of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
  • Tablets can be prepared, for example, from the following ingredients:
  • the active compound, the lactose and some of the starch can be de-aggregated, blended and the resulting mixture can be granulated with a solution of the polyvinylpyrrolidone in ethanol.
  • the dry granulate can be blended with the magnesium stearate and the rest of the starch.
  • the mixture is then compressed in a tabletting machine to give tablets each containing a unit dose or a part of a unit dose of active compound.
  • Tablets can be prepared by the method described in (b) above.
  • the tablets can be enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanohdichloromethane (1: 1). d) Suppositories
  • suppositories for example, 100 parts by weight of active compound can be incorporated in 1300 parts by weight of triglyceride suppository base and the mixture formed into suppositories each containing a therapeutically effective amount of active ingredient.
  • the present invention also comprises the use of a compound of Formula I as a medicament.
  • a further aspect of the present invention provides the use of a compound of Formula I or a salt thereof in the manufacture of a medicament for treating vascular hyperpermeability, angiogenesis-dependent disorders, proliferative diseases and/or disorders of the immune system in mammals, particularly human beings.
  • the present invention also provides a method of treating vascular hyperpermeability, inappropriate neovascularization, proliferative diseases and/or disorders of the immune system which comprises the administration of a therapeutically effective amount of a compound of Formula I to a mammal, particularly a human being, in need thereof.
  • the [ 35 S]GTPyS binding assay was performed using both scintillation proximity assay (SPA) and filtration methods. Both formats are advantageously run in 96 well plates and utilize membranes from stable or transient CHO human cell lines overexpressing SlPi, SlP 2 , SlP 3 , SlP 4 or SlP 5 . Compound stocks were made up to 10 mM using DMSO and serial dilutions were carried out using 100% DMSO. Compounds were transferred to 96 well plates to yield a final DMSO concentration of 1% for all assays (IuI for a lOOul assay volume).
  • SPA scintillation proximity assay
  • Frozen membranes were thawed and diluted in assay buffer containing of 20 mM HEPES pH 7.4, 0.1% fatty acid-free BSA, 10OmM NaCl, 5mM MgCl 2 and 10 ⁇ M GDP.
  • Assay buffer containing of 20 mM HEPES pH 7.4, 0.1% fatty acid-free BSA, 10OmM NaCl, 5mM MgCl 2 and 10 ⁇ M GDP.
  • SPA assay membranes are premixed with WGA-SPA beads to yield a final concentration per well of 5ug membrane and 500ug of bead.
  • membranes are added directly to the incubation plate at 5ug per well. The assay begins with the addition of 50ul of the membrane or membrane/bead mixture to each well of the assay plate. Next, 50ul of 0.4nM [ 35 S]GTPyS is added to each well and incubated for 30 minutes.
  • Nonspecific binding is measured using lOuM unlabeled GTPyS.
  • SPA the plates are spun and then read on the Topcount.
  • filtration assay the plate is harvested onto GF-C filtration plates using a Packard 96 well harvester.
  • Radio ligand binding was carried out using membranes from transiently transfected HEK cells overexpressing SlPi, SlP 2 , SlP 3 , SlP 4 or SlP 5 . All compounds are dissolved in DMSO and serial dilutions were carried out in DMSO prior to addition to assay buffer. Final assay DMSO concentrations are 1% (v/v).
  • [ 33 P]SlP is purchased from Perkin Elmer and used at 50 pM in all assays. Frozen membranes are thawed and resuspended in assay buffer caontaining 50 mM HEPES pH7.4, 10OmM NaCl, 1OmM MgCl 2 and 0.1% fatty acid free BSA.
  • Membrane is added to give 5- 10 ug of membrane per well. Non-specific binding is determined in the presence of cold 1 uM SlP. Incubations are carried out at room temperature for 45-60 minutes before filtering onto GF/C filtration plates using a Packard 96 well harvester. Plates are dried before adding Microscint to each well, sealed and counted on a Topcount.
  • mobile phase A was 10 mM ammonium acetate
  • mobile phase B was HPLC grade acetonitrile.
  • the column used for the chromatography is a 4.6x30 mm Vydac Genesis C8 column (4 ⁇ m particles). The gradient was 5-60% B in 1.5 min then 60-95% B to 2.5 min with a hold at 95% B for 1.2 min (1.3 mL/min flow rate).
  • Mobile phase A was water with 0.1% formic acid
  • mobile phase B was HPLC grade acetonitrile.
  • Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as pos/neg electrospray ionization.
  • DAD diode array
  • ELSD evaporative light scattering
  • Example D.2 The general procedure letter codes constitute a synthetic route to the final product.
  • a worked example of how the route is determined is given below using Example D.2 as a non- limiting illustration.
  • the synthesis of Example D.2 was completed using general procedure H as detailed in Table D, i.e.,
  • the starting material was prepared using the route (A, B, I, J, E, F, G) (as detailed in Table C).
  • ester starting material used in general procedure H is the product of following the procedures A, I, J, E, F and G, in the given order.
  • a rhodium catalyst such as hydroxyl[(S)-BINAP]rodium(I) dimmer, or Rh(acac)(C 2 H 4 ) 2 /(/?)- BINAP (preferably
  • 2- cyclopenten-1-one is added to the mixture.
  • the reaction is stirred at about 20 - 100 0 C (preferably about 35 0 C) for a period of 1 - 24 hours (preferably about 16 hours) under inert atmosphere.
  • the reaction mixture is concentrated under reduced pressure and the crude product is purified via flash chromatography.
  • a base such as potassium carbonate, or sodium carbonate
  • an organic solvent such as DMF, or DMA
  • DMF dimethyl iodide
  • the reaction is stirred at room temperature for a period of 24 - 72 hours (preferably about 48 hours).
  • the reaction mixture is concentrated, cooled down with ice-water bath and water is added.
  • the precipitate is collected by filtration to give the crude product.
  • the two stereoisomers can be separated by crystallization.
  • the two diastereomers can be separated by crystallization as follows: The material was separated into 2 batches of 110 g each. The crude material (110 g) was suspended in ACN (2.5 L), heated to 70 0 C until near complete dissolution occurred. The material was filtered rapidly at 70 0 C and rinsed with 70 0 C ACN (2 x 500 mL). The combined filtrates were reheated to about 65 0 C with stirring. After a clear solution was obtained the mixture was allowed to cool slowly to 50 0 C at which point material began to drop out of solution. The solution was allowed to slowly cool to 30 0 C with stirring (100 rpm).
  • N-alkylated hydantoin (1 equivalent) in water is added dioxane and an inorganic base (such as lithium hydroxide, or sodium hydroxide) (5 - 15 equivalents, preferably about 8 - 10 equivalents).
  • an inorganic base such as lithium hydroxide, or sodium hydroxide
  • the mixture is heated to reflux for a period of 16 - 48 hours (preferably 24 hours).
  • the reaction mixture is acidified, and filtered.
  • the filter cake is washed with a suitable solvent and dried under vacuum to give the corresponding amino acid.
  • an organic base such as piperidine, diethylamine or triethylamine
  • an organic solvent such as tetrahydrofuran, dioxane or DMF (preferably tetrahydrofuran).
  • the mixture is degassed before adding a palladium catalyst (such as tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)palladium(II) chloride) (2 - 10 mol %, preferably 5 mol %) and copper® iodide (2 -10 mol %, preferably 5 mol %).
  • a palladium catalyst such as tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)palladium(II) chloride
  • the reaction mixture is heated at 45 - 110 0 C (preferably about 60 0 C) for a period of 4 - 48 hours (preferably 24 - 36 hours) under inert atmosphere.
  • more alkyne compound (1 - 8 equivalents, preferably 2 - 4 equivalents) is added in portions to the reaction mixture to drive the reaction to completion.
  • the mixture Upon completion of the reaction, the mixture is concentrated to dryness, dissolved in a suitable organic solvent (such as EtOAc, or DCM), and washed with a saturated aqueous solution of NaHCO 3 , dried over an appropriate drying reagent (such as MgSO 4 , or Na 2 SO 4 ) and concentrated to dryness to give the crude product.
  • a suitable organic solvent such as EtOAc, or DCM
  • an appropriate drying reagent such as MgSO 4 , or Na 2 SO 4
  • reaction vessel charged with palladium hydroxide on carbon (10 - 30 % by weight, preferably 20 % by weight) is added acetic acid and an alkyne compound (1 equivalent).
  • the reaction mixture is evacuated, back-filled with nitrogen followed by two cycles of evacuating and back-filling with hydrogen gas.
  • the reaction is charged to about 30 - 60 psi (preferably about 50 psi) with hydrogen and is shaken at room temperature for a period of 0.5 - 24 hours (preferably about 1 hour).
  • the crude mixture is filtered, washed with a suitable solvent such as ethanol, and concentrated. The residue can be purified by crystallization with ethanol/water mixture to give the desired product.
  • the crude mixture was filtered through Celite® and washed with ethanol. The filtrate was concentrated, and the residue was brought up in a small amount of ethanol. Water was added. The mixture was nearly clear. The ethanol was removed under reduced pressure, and the remainingaqueous solution was left to stand. After a few minutes, needle-like crystals began to form. More water was added, and the mixture left to crystallize. The white solid was collected by filtration, and washed with water three times. The white solid was freeze-dried to remove remaining water.
  • a substituted 1-amino-cyclopentanecarboxylic acid methyl ester dissolved in a suitable solvent is cooled to below room temperature (about 0 - 10 0 C, preferably 0 0 C).
  • a suitable solvent such as tetrahydrofuran or ether
  • LAH reducing reagent
  • the reaction mixture is stirred for a period of 0.5 - 6 hours (preferably 0.5 - 2 hours).
  • the reaction mixture is worked up by successive addition of n mL of water, n mL of 2 M NaOH solution, and 2n mL of water for n g of LAH used in the reaction. After stirred for a period of 1 -24 hours (preferably 2 hours), Na 2 SO 4 is added and the precipitate is filtered off.
  • the product precipitates out as hydrochloride by adding HCl to the filtrate.
  • a substituted l-amino-cyclopentanecarbonitrile in 6 M hydrochloric acid and dioxane is heated at 80 - 110 0 C (preferably about 100 0 C) for a period of 12 - 24 hours (preferably 16 hours).
  • the reaction mixture is cooled on ice.
  • the precipitate is collected by filtration and washed with water to give the desired product.
  • a methyl ether compound in a suitable solvent such as dichloromethane, or dichloroethane
  • a suitable solvent such as dichloromethane, or dichloroethane
  • BBr 3 (1 - 5 equivalents, preferably 3 equivalents
  • the reaction mixture is stirred at about 0 0 C for a period of 0.5 - 2 hours (preferably 0.5 hour).
  • the reaction is quenched with a protic solvent such as methanol or water, warmed up to room temperature, and concentrated to dryness.
  • the residue is triturated with water, filtered to give the desired product.
  • a solution of a phenol, an alcohol (1 - 3 equivalents, preferably 1.1 equivalents) and resin bound triphenylphospine (1 - 3 equivalents, preferably 2.2 equivalents) in a suitable solvent (such as tetrahydrofuran, dichloromethane) is cooled to about 0 0 C.
  • An azodicarboxylate such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, or di-t ⁇ rz-butyl azodicarboxylate
  • the reaction is warmed up to room temperature and shaken for a period of 2 - 24 hours (preferably 3 hours).
  • the resin is filtered off and rinsed with a suitable solvent (such as tetrahydrofuran, dichloromethane).
  • the filtrate is concentrated to dryness.
  • the crude product is further purified via flash chromatography.
  • a suitable solvent such as dioxane, or tetrahydrofuran
  • an inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide
  • the reaction is concentrated, partitioned between a suitable organic solvent (such as ether, or ethyl acetate) and water.
  • the organic layer is dried over an appropriate drying reagent (such as Na 2 SO 4 , MgSO 4 ), filtered and concentrated.
  • the product can be isolated as an ammonium salt by treating the residue with an inorganic acid (such as HCl).
  • phosphate ester intermediate is taken up in a solution of HBr in acetic acid, stirred at 0-50 0 C (preferably room temperature) for 1-30 minutes (preferably 5 minutes) then concentrated.
  • the residue is triturated with a suitable organic solvent such as ether, ethyl acetate or acetonitrile (preferably acetonitrile), then is triturated with dilute aqueous ammonium acetate solution, filtered and dried.
  • a suitable organic solvent such as ether, ethyl acetate or acetonitrile (preferably acetonitrile)
  • a suitable solvent such as tetrahydrofuran, dioxane
  • a strong base such as LiHMDS, NaH
  • Tetrabenzyl diphosphate (1 - 1.5 equivalents, preferably 1.0 equivalents) is added to the mixture and the reaction mixture is stirred at room temperature for a period of 0.5 - 4 hours (preferably 2 hour).
  • the reaction is briefly cooled to about 0 0 C and the precipitated solid is removed by filtration and the filtrate is concentrated.
  • the residue is taken up in a solution of HBr in acetic acid, stirred at 0-50°C (preferably room temperature) for 1-30 minutes (preferably 5 minutes) then concentrated.
  • the residue is triturated with a suitable organic solvent such as ether, ethyl acetate or acetonitrile (preferably acetonitrile), then is triturated with dilute aqueous ammonium acetate solution, filtered and dried.
  • a suitable solvent such as tetrahydrofuran, dioxane
  • a suitable inorganic base such as lithium hydroxide, sodium hydroxide
  • the mixture is heated at 45 - 65 0 C (preferably 50 0 C) for a period of 2 - 24 hours (preferably 4 - 5 hours).
  • the crude reaction is acidified with acid.
  • the precipitate is collected by filtration, washed with ether and water, dried to give the desired product.
  • a solution of substituted phenol in an organic solvent (such as tetrahydrofuran, DMF or dioxane) (preferably DMF) is added dropwise to a stirred suspension of Sodium Hydride in the same solvent at -10-30 0 C, preferably about 0 0 C under an inert atmosphere.
  • the alkylating agent for example Ethyl bromoacetate, Iodomethane, Iodoethane or tert-Butyl bromoacetate, is added dropwise to the stirred anion and then the reaction is warmed to 20-100 0 C, preferably room temperature for 1-24 hours. The reaction is then concentrated under reduced pressure and the crude product is taken up in Ethyl acetate, washed with water, dried (Na 2 SO 4 ), filtered, concentrated and further purified via flash chromatography.
  • a solution of carboxylic acid in an organic solvent (such as tetrahydrofuran or dioxane) (preferably THF) is added dropwise to a stirred solution of borane in THF at 0-50 0 C, preferably about 23°C under an inert atmosphere.
  • the reaction is stirred at warmed to 20-50 0 C, preferably room temperature for 1-24 hours.
  • the reaction is then quenched by cautious addition of methanol at 0-50 0 C, preferably about room temperature.
  • the crude product is concentrated under reduced pressure, taken up in ethyl acetate, washed with water, dried (Na 2 SO 4 ), filtered, and concentrated
  • a boronic acid (1 - 3 equivalents, preferably 1 equivalents) and an inorganic base (cesium carbonate or sodium carbonate) (preferably cesium carbonate) (3 - 8 equivalents, preferably 3 equivalents) is added an organic solvent (such as 1,2-dimethoxyethane, dioxane or DMF; preferably 1,2-dimethoxyethane) and water mixture (about 10: 1 to 1: 1 ratio; preferably 4: 1 ratio).
  • an organic solvent such as 1,2-dimethoxyethane, dioxane or DMF; preferably 1,2-dimethoxyethane
  • the mixture is degassed before adding a palladium catalyst (such as tetrakis(triphenylphosphine)palladium, l,l'-bis(diphenylphosphino)ferrocene palladium dichloride or bis(triphenylphosphine)palladium(II) chloride; preferably l,l'-bis(diphenylphosphino) ferrocene palladium dichloride) (2 - 10 mol %, preferably 5 mol %).
  • a palladium catalyst such as tetrakis(triphenylphosphine)palladium, l,l'-bis(diphenylphosphino)ferrocene palladium dichloride or bis(triphenylphosphine)palladium(II) chloride; preferably l,l'-bis(diphenylphosphino) ferrocene palladium dichloride) (2 - 10 mol %,
  • the mixture is concentrated to dryness, dissolved in a suitable organic solvent (such as EtOAc, or DCM), and washed with a saturated aqueous solution of NaHCO 3 , dried over an appropriate drying reagent (such as MgSO 4 , or Na 2 SO 4 ) and concentrated to dryness to give the crude product.
  • a suitable organic solvent such as EtOAc, or DCM
  • an appropriate drying reagent such as MgSO 4 , or Na 2 SO 4
  • aqueous sodium hydroxide solution (about 4 - 12 equivalents, preferably 8 equivalents) and 30% w/v hydrogen peroxide solution (about 4 - 12 equivalents, preferably 8 equivalents) is then poured into the rection mixture. Stirring is continued for a period of 1 - 8 hours (preferably 2 hours). The solvent is removed under reduced pressure and the resulting crude can be purified by flash chromatography to afford the desired product.
  • a Cbz-protected amine dissolved in an organic solvent such as methanol, ethanol or ethyl acetate; preferably ethanol
  • an organic solvent such as methanol, ethanol or ethyl acetate; preferably ethanol
  • the hydrogen gas is bubbled through the reaction for about 5 minutes.
  • the reaction is stirred under the atmosphere of hydrogen for a period of 1 - 48 hours (preferably 2 - 24 hours).
  • the progress of the reaction is monitored via LCMS.
  • the resulting crude reaction mixture is filtered through Celite® and the filtrate is concentrated in vacuo to yield crude product, which can be further purified via column chromatography or used as is for the next step.
  • organometalic reagent (1-3 equivalents, preferably 1.1 equivalents) is added to a solution of a beta-alkoxy enone in an organic solvent (preferably THF) at about -78 °C-room temperature (preferably 0 0 C). Following the addition the reaction mixture is allowed to warm to about room temperature. After Ih IN HCl is added until a pH of 1 is obtained. The reaction mixture is taken through an aqueous work-up and the crude product can be purified by chromatography.
  • organic solvent preferably THF
  • the reaction mixture was diluted with Et 2 O and the organic layer was separated, washed with NaHCO 3 , and brine, dried with Na 2 SO 4 , filtered and concentrated in vacuo.
  • the crude product was purified by chromatography on silica gel (EtOAc/Hep) to provide 3-(4-octylphenyl)cyclohex-2 -enone (9.5 g, 33.4 mmol, 65.9 % yield) as a colorless oil.
  • an ester in an organic solvent preferably THF
  • an organometallic reagent 2-10 equivalents, preferably 5 equivalents.
  • the reaction mixture is quenched with water and the crude product is extracted into a suitable organic solvent (preferably ether).
  • a suitable organic solvent preferably ether
  • the aqueous layer was extracted with Et 2 O (100 mL) sonicating for 15 min to break up the emulsion.
  • the combined organic layers were dried (Na 2 SO 4 ) filtered and cone, in vacuo.
  • the crude product was purified by chromatography on silica gel (40 g) eluting with DCM:MeOH:HOAc:H 2 O (900:90:9: 1). The fractions containing the product were combined and concentrated in vacuo.
  • the resulting alkene was added to a slurry of palladium hydroxide on carbon (4.49 mg, 0.032 mmol) in MeOH (10.00 mL). Hydrogen was bubbled through the solution for 5 min and an atmosphere of hydrogen was maintained via balloon. After 15h the reaction mixture was filtered and concentrated in vacuo. The crude alkane was purified by chromatography on silica gel (EtOAc/Hep) to provide (5R,7R)-7-(4-(7-methyloctyl)phenyl)-3-oxa-l- azaspiro[4.4]nonan-2-one (120 mg, 0.349 mmol, 54.6 % yield) as a colorless solid.
  • a strong base preferably sodium hydride 0.5-2 equivalents (preferably 1 equivalent) in a suitable solvent (preferably DMF) is added an alkylating agent 1-5 equivalents (preferably 1.2 equivalent) followed by a solution of an alcohol. After the reaction is substantively complete the reaction mixture is taken through an aqueous work up and purified by chromatography or distillation.
  • l,4-dibromobutan-2-ol (0.5-2 equivalents, preferably 1.1 equivalent), an aniline (0.5-2 equivalents, preferably 1.0 equivalent), potassium carbonate (0.5-2 equivalents, preferably 1.1 equivalent) and a polar protic solvent (preferably water).
  • the reaction vial is heated in a microwave at (50-200 watts, preferably 100 watt), (50-200 0 C, preferably 120 0 C, (100-200 psi, preferably 150 psi), (ramp time of 2-10 min, preferably 5 min) and (hold time of 10-30 min, preferably 20 min).
  • an organic solvent preferably EtOAc
  • the organic layer is removed and concentrated in vacuo.
  • the crude product is purified by flash chromatography on silica gel.
  • the product was purified by flash chromatography on silica gel (eluting with EtO Ac/Hep) to provide 1- (4-octylphenyl)pyrrolidin-3-ol (3.7 g, 13.43 mmol, 53.7 % yield) as a white solid which was stored under nitrogen in a sealed flask.
  • a weak organic base preferably pyridine, 2-5 equivalents, preferably 3.5 equivalents
  • a carbodiimide preferably DCC, 1-3 equivalents, preferably 1.75 equivalents
  • an organic acid preferably TFA, 0.5-2 equivalents, preferably 1 equivalents
  • heptane extracts were purified by silica gel chromatography eluting with EtOAc/Hep to provide l-(4-octylphenyl)pyrrolidin-3-one (3.1 g, 11.34 mmol, 84 % yield) as a colorless solid.
  • Reaction is then filtered to remove the resin-bound borohydride and the resin washed 3 x with a suitable solvent (such as dichloromethane, methanol, tetrahydrofuran, or dimethylformamide, preferably methanol).
  • a suitable solvent such as dichloromethane, methanol, tetrahydrofuran, or dimethylformamide, preferably methanol.
  • the filtrate is collected, concentrated and chromatographed to give the desired product.
  • the aqueous layer was back-extracted with diethyl ether (150 mL).
  • the combined organic phase was wash with brine (15OmL), dried (MgSO 4 ) and concentrated to yield 5.89 g of colorless liquid.
  • the crude liquid was purified via Analogix FCC system using Biotage RS 330g column, with a gradient of 0-50% ether/pet, ether over 10 min. at 40 mL/min. then held at 50% for 50 min. Fractions containing product were combined and concentrated to yield hept-6-yn- l-ol (4.94 g, 44.0 mmol) as colorless liquid.
  • the title compound was also prepared according to procedure described by B. W.
  • the flask was evacuated and filled with nitrogen and then acetonitrile (12 mL) and 1- octyne (0.228 g, 2.07 mmol) were each added dropwise via syringe. The resulting mixture was heated at 100 °C for 72 h. The reaction was allowed to cool to rt and filtered through a pad of celite.

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Abstract

L'invention concerne de nouveaux et puissants agents sélectifs étant des agonistes ou des antagonistes d'un ou plusieurs récepteurs individuels de la famille des récepteurs de S1P. Les composés selon l'invention servent d'agents thérapeutiques pour traiter des troubles médicaux associés à l'agonisme ou à l'antagonisme des récepteurs individuels de la famille des récepteurs de S1P.
PCT/US2007/026263 2006-12-21 2007-12-21 Composés d'agonistes et d'antagonistes des récepteurs de sphingosine-1-phosphate WO2008079382A1 (fr)

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CA002672727A CA2672727A1 (fr) 2006-12-21 2007-12-21 Composes d'agonistes et d'antagonistes des recepteurs de sphingosine-1-phosphate
JP2009542960A JP2010513532A (ja) 2006-12-21 2007-12-21 スフィンゴシン−１−ホスフェート受容体作働薬および拮抗薬化合物
MX2009006751A MX2009006751A (es) 2006-12-21 2007-12-21 Compuestos agonistas y antagonistas del receptor de esfingosina-1-fosfato.
AU2007338700A AU2007338700A1 (en) 2006-12-21 2007-12-21 Sphingosine-1 -phosphate receptor agonist and antagonist compounds
EP07863237A EP2120575A4 (fr) 2006-12-21 2007-12-21 Composés d'agonistes et d'antagonistes des récepteurs de sphingosine-1-phosphate
BRPI0720478-7A BRPI0720478A2 (pt) 2006-12-21 2007-12-21 Compostos agonistas e antagonistas do receptor esfingosina-1-fosfato
EC2009009435A ECSP099435A (es) 2006-12-21 2009-06-15 Compuestos agonistas de receptores esfingosina-1-fosfato y compuestos antagonistas
NO20092376A NO20092376L (no) 2006-12-21 2009-06-22 Sfingosin-1-fosfat-reseptoragonist og -antagonistforbindelser

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US8173710B2 (en) 2006-02-09 2012-05-08 University Of Virginia Patent Foundation Bicyclic sphingosine 1-phosphate analogs
US7915315B2 (en) 2006-11-21 2011-03-29 University Of Virginia Patent Foundation Benzocycloheptyl analogs having sphingosine 1-phosphate receptor activity
US7964649B2 (en) 2006-11-21 2011-06-21 University Of Virginia Patent Foundation Hydrindane analogs having sphingosine 1-phosphate receptor agonist activity
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RU2009128062A (ru) 2011-01-27
TW200838497A (en) 2008-10-01
CL2007003784A1 (es) 2008-06-27
DOP2009000149A (es) 2010-05-15
BRPI0720478A2 (pt) 2014-01-14
AU2007338700A1 (en) 2008-07-03
ECSP099435A (es) 2009-07-31
CR10872A (es) 2009-07-23
PE20081561A1 (es) 2008-10-30
EP2120575A1 (fr) 2009-11-25
CA2672727A1 (fr) 2008-07-03
JP2010513532A (ja) 2010-04-30
UY30829A1 (es) 2008-07-31
NO20092376L (no) 2009-06-22
MX2009006751A (es) 2009-06-30
AR064650A1 (es) 2009-04-15

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