WO2011071570A1 - Composés inédits d'oxadiazole - Google Patents

Composés inédits d'oxadiazole Download PDF

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Publication number
WO2011071570A1
WO2011071570A1 PCT/US2010/046424 US2010046424W WO2011071570A1 WO 2011071570 A1 WO2011071570 A1 WO 2011071570A1 US 2010046424 W US2010046424 W US 2010046424W WO 2011071570 A1 WO2011071570 A1 WO 2011071570A1
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Prior art keywords
optionally substituted
oxadiazol
chloro
isopropoxyphenyl
acid
Prior art date
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PCT/US2010/046424
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English (en)
Inventor
Kevin P. Cusack
Eric C. Breinlinger
Shannon R. Fix-Stenzel
Robert H. Stoffel
Kevin R. Woller
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Abbott Laboratories
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Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to CA2783851A priority Critical patent/CA2783851A1/fr
Priority to EP10836346.6A priority patent/EP2509424A4/fr
Priority to JP2012543093A priority patent/JP2013512951A/ja
Priority to MX2012006667A priority patent/MX2012006667A/es
Priority to CN2010800633803A priority patent/CN102762102A/zh
Publication of WO2011071570A1 publication Critical patent/WO2011071570A1/fr

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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • A61P5/00—Drugs for disorders of the endocrine system
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    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Sphingosine-1 -phosphate is part of sphingomyelin biosynthetic pathway and is known to affect multiple biological processes. SIP is formed through phosphorylation of sphingosine by sphingosine kinases (SKI 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
  • SIP evokes many responses from cells and tissues.
  • SIP has been shown to be an agonist at all five GPCRs, S1P1 (Edg-1), S1P2 (Edg-5), S1P3 (Edg-3), S1P4 (Edg-6) and S1P5 (Edg-8).
  • the action of SIP at the SIP 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, SIP receptors are targets for therapy of, for example, neoplastic diseases, autoimmune disorders and tissue rejection in transplantation. These receptors also share 50-55% amino acid identity with three other lysophospholipid receptors, LPA1, LPA2, and LPA3 of the structurally related lysophosphatidic acid (LPA).
  • 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.
  • the response specificity of the SIP receptors could allow for an SIP 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 SIP receptors have been limited.
  • SIPl for example is widely expressed and the knockout causes embryonic lethality due to large vessel rupture.
  • Adoptive cell transfer experiments using lymphocytes from SIPl knockout mice have shown that SIPl deficient lymphocytes sequester to secondary lymph organs. Conversely, T cells overexpressing SIPl partition preferentially into the blood compartment rather than secondary lymph organs.
  • the present invention provides novel compounds described by general Formula (I), (la), (II), (III), (IV), (Iva), (IVb) or (V) as agonists of the G protein-coupled receptor SIPl . These compounds reduce the number of circulating and infiltrating T- and B-lymphocytes affording a beneficial immunosuppressive effect. The compounds also exhibit activity within the SIP receptor family.
  • the invention provides a compound of Formula (I)
  • R 1 is -C(0)-NH-phenyl, -NH-C(0)-furanyl, -NH-S(0) 2 -optionally substituted phenyl, -O- optionally substituted (Ci-C 3 )alkyl, -S-optionally substituted (Ci-C 3 )alkyl, optionally substituted (C 2 -C 6 )alkyl, optionally substituted amino, optionally substituted (C 3 -C 6 )cycloalkyl, - (CH 2 )(C 3 )alkyl, optionally substituted tetrahydrobenzofuranyl, optionally substituted furanyl, optionally substituted tetrahydrofuranyl, optionally substituted 2,3-dihydroisoindolyl, optionally substituted isoindolinyl, optionally substituted imidazolyl, optionally substituted 5,6-dihydro imidazo[l,2-a]pyrazinyl, optionally substituted imidazo[
  • R 2 is Br, CI, CF 3 , CN, or -0-(Ci-C 2 )alkyl
  • R 3 is optionally substituted-(C 3 -C 8 )alkyl, deuterated -(C 2 -C 6 )alkyl, (C 4 -C 5 )alkenyl, (C 4 - C 5 )alkynyl, optionally substituted-(C 3 -C 6 )cycloalkyl, -optionally substituted (C 2 -C 3 )alkyl-0- optionally substituted (Ci_C 3 )alkyl, -optionally substituted (Ci-C 3 )alkyl-imidazolyl, -optionally substituted (C l -C 3 )alkyl-mo holinyl, -optionally substituted (Ci-C 3 )alkyl-optionally substituted phenyl, -optionally substituted (Ci-C 3 )alkyl-optionally substituted piperazinyl, -optionally substituted (Ci-C 3 )alkyl-pyrrolidiny
  • R 6 is H
  • R 1 is not substituted by optionally substituted cyclohexyl, -C(0)-cyclohexyl or -NH- cyclohexyl;
  • R 1 is not optionally substituted isoxazolyl
  • L-R 1 is not cyclohexyl or -CH 2 -cyclohexyl
  • each R 9 is independently selected from H or optionally substituted (Ci-C 6 )alkyl.
  • the invention provides a compound according to any of the foregoing embodiments wherein the compound is a compound of Formula (la)
  • the invention provides a compound according to any of the foregoing embodiments wherein R 1 is optionally substituted tetrahydrobenzofuranyl, optionally substituted furanyl, optionally substituted 2,3-dihydroisoindolyl, optionally substituted isoindolinyl, optionally substituted imidazolyl, optionally substituted 5,6-dihydro imidazo[l,2- a]pyrazinyl, optionally substituted imidazo[l , 2 -a]pyrazinyl, optionally substituted indolyl, optionally substituted isoxazolyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, optionally substituted 1,2,3,4-tetrahydroisoquinolinyl, optionally substituted quinolinyl, optionally substituted 3,4-dihydroquinolinyl, optionally substituted
  • the invention provides a compound according to any of the foregoing embodiments wherein R 1 is optionally substituted furanyl, optionally substituted imidazolyl, optionally substituted isoxazolyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, optionally substituted pyrrolyl, optionally substituted thiazolyl or optionally substituted thienyl.
  • the invention provides a compound according to any of the foregoing embodiments wherein R 1 is optionally substituted phenyl or optionally substituted indolyl.
  • L is optionally substituted (Ci-C 3 )alkyl
  • R 1 is -C(0)-NH-phenyl, -NH-C(0)-furanyl, -NH-S(0) 2 -optionally substituted phenyl, optionally substituted -0-(Ci-C 3 )alkyl, -S-(Ci-C 3 )alkyl, optionally substituted benzyloxy, optionally substituted(C 3 -C 6 )cycloalkyl, optionally substituted imidazolyl, morpholinyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted pyridinyl, optionally substituted pyrrolidinyl or optionally substituted thienyl;
  • R 2 is CI
  • R 3 is isopropyl
  • R 6 is H.
  • the invention provides a compound of according to any of the foregoing embodiments wherein L is CH 2 and R 1 is optionally substituted phenyl or optionally substituted (C 3 -C 6 )cycloalkyl.
  • L is a bond or CH 2 ;
  • R 1 is optionally substituted (Ci-C 4 )alkyl, optionally substituted indolyl or optionally substituted phenyl;
  • R 2 is CF 3 ,
  • R 3 is H, morpholinyl, optionally substituted piperidine or (C 3 -C 5 )cycloalkyl; and R 6 is H.
  • the invention provides a compound according to the tenth embodiment wherein R 1 is optionally substituted by one or more substituents independently selected from CI, F, CN, optionally substituted (Ci-C 3 )alkyl,-CH 2 -optionally substituted azetidinyl, -CH 2 -optionally substituted pyrrolidinyl, -CH 2 NR c R d , -NH-optionally substituted (C 3 - C 6 )cycloalkyl, optionally substituted piperidinyl,
  • R c and R d are independently H, optionally substituted (Ci-C6)alkyl or optionally substituted (C3-C6)cycloalkyl;
  • the invention provides a compound of Formula (III)
  • E is CH or N
  • L is a bond
  • R 1 is optionally substituted aryl
  • R 2 is H
  • R 3 is H
  • R 6 is H or optionally substituted (Ci-C 3 )alkyl.
  • X is N or CR 4 ;
  • L is a bond, -CH 2 CH 2 -, (C 3 -C 6 )cycloalkyl, or -CHR 5 ;
  • Y is -0-, -NR 7 - or -C(R 7 )(R 7' )-;
  • R 1 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted -(Ci-C 6 )alkyl-0-(Ci-C 3 )alkyl, optionally substituted -(Ci- C 6 )alkyl-0-(Ci-C 6 )alkyl -0-(C C 3 )alkyl, optionally substituted -(Ci-C 6 )alkyl-0-aryl, alkylsulfanylalkyl, unsubstituted (C 2 -C 5 )alkyl, substituted (Ci-C 6 )alkyl, -COR 11 , optionally substituted -0-(Ci-C 3 )alkyl, -N(R 7 )(R 8 ), -N(R 7 )S0 2 -R n or optionally substituted (C 3 - C 6 )cycloalkyl, and wherein R 1 is not substituted
  • R 2 and R 6 may be the same or different and are independently H, -(Ci-C alkyl, -0-(Ci- C 3 )alkyl, -CF 3 , -CN, halo or -COO-(Ci-C 4 )alkyl;
  • R 3 is optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted (C 3 -C 6 )cycloalkyl, -(CH 2 ) n -R n , -CO-OR 11 , -CO-R 11 , - CON(R 7 )(R n ), -N(R 7 )(R n ), -SOR 11 , -S0 2 R n and optionally substituted straight or branched (Q- C 8 )alkyl chain optionally including -CO-, -COO-, -SO-, -S0 2 -, -CONH-, -NHCO-, -N- or -O- groups embedded within the alkyl chain; and when Y is O, R 3 is not alkyldiazeapane, - C(CH 3 ) 2 COOCH 2 CH 3 or -CH 2 CH 2 N(CH 2 CH 3 ) 2;
  • R 4 is H, -(Ci-C 4 )alkyl, -0-(Ci-C 3 )alkyl, -CF 3 , -CN or halo;
  • R 5 is H, 0-(Ci-C 3 )alkyl or (Ci-C 3 )alkyl;
  • each occurrence of R 7 or R 7 is independently H or optionally substituted (Ci-C 3 )alkyl;
  • R 8 is H, optionally substituted CH 3; or -COR 11 ;
  • R 11 is hydrogen, optionally substituted (Ci-C 3 )alkyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl or optionally substituted (C 3 -C 6 )cycloalkyl; and n is 1 , 2, 3 or 4;
  • R 1 is not optionally substituted furanyl or -C(O) -optionally substituted furanyl
  • R 3 is not optionally substituted quinolinyl
  • R n is not optionally substituted cyclopropyl, optionally substituted cyclohexyl, optionally substituted furanyl, optionally substituted imidazolyl, optionally substituted indolyl, optionally substituted naphthyl, optionally substituted piperazinyl, optionally substituted pyrazolyl, optionally substituted pyridazinyl or optionally substituted quinolinyl;
  • R 1 is not substituted by -C(0)-cyclopentyl, optionally substituted cyclopentyl, -C(O)- cyclobutyl, cyclobutyl, -C(0)-cyclohexyl or optionally substituted cyclohexyl;
  • R 3 is not substituted by -C(0)-cyclopropyl
  • L-R 1 is not cyclopropyl, cyclopentyl, optionally substituted cyclohexyl, -CH 2 -cyclohexyl, -NH-cyclohexyl, -CH 2 CH 2 -cyclohexyl or optionally substituted pyrazolyl;
  • R 3 is not -(C 0 -C 4 )alkyl-optionally substituted isoxazolyl or optionally substituted pyrazolyl;
  • R 1 is not optionally substituted isoxazolyl
  • R 1 is not optionally substituted cyclobutyl, optionally substituted cyclohexyl, optionally substituted naphthyl, -CH 2 -optionally substituted naphthyl, -CH 2 -0- optionally substituted naphthyl, optionally substituted pyrazolyl or tetrahydrobenzofuranyl; rovided the compound is not
  • R 3 is optionally substituted piperazinyl or optionally substituted phenyl
  • R 1 is optionally substituted pyridine or 3-chlorophenyl and -Y-R 3 is
  • L is CH 2 , CH(CH 3 ) or CH 2 CH 2 ;
  • Y is O or CH 2 ;
  • R 2 is H or OCH 3 ;
  • R 3 is CH 3 or OCF 3 ;
  • R is H or N0 2 ;
  • R 1 is phenyl, 4-chlorophenyl, piperidinyl or thienyl.
  • the invention provides a compound according t the fourteenth embodiment wherein
  • R 1 is optionally substituted phenyl, optionally substituted tetrahydrobenzofuranyl, optionally substituted furanyl, optionally substituted 2,3-dihydroisoindolyl, optionally substituted isoindolinyl, optionally substituted imidazolyl, optionally substituted 5,6-dihydro imidazo[l,2- a]pyrazinyl, optionally substituted imidazo[l,2-a]pyrazinyl, optionally substituted indolyl, optionally substituted isoxazolyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, optionally substituted 1,2,3,4-tetrahydroisoquinolinyl, optionally substituted quinolinyl, optionally substituted 3,4-dihydroquinolinyl, optionally substituted 3,4-dihydroisoquinoliny
  • R 2 and R 6 may be the same or different and are independently H, -(Ci-C alkyl, -0-(Ci- C 3 )alkyl, -CF 3 , -CN, CI, or F.
  • L is a bond, -CH 2 CH 2 -, or -CHR 5 ;
  • Y is -0-, -NR 7 - or -C(R 7 )(R 7' )-;
  • R 1 is optionally substituted phenyl, T optionally substituted furanyl, optionally substituted isoindolinyl, optionally substituted imidazolyl, optionally substituted imidazo[l,2-a]pyrazinyl, optionally substituted indolyl, optionally substituted isoxazolyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, -, optionally substituted quinolinyl, optionally substituted pyrrolyl, optionally substituted pyrrolo[2,3-b]pyridinyl, optionally substituted quinolinyl, optionally substituted thiazolyl, optionally substituted thienyl, optionally substituted -(Ci-C 6 )alkyl-0-(Ci-C 3 )alkyl, optionally substituted -(Ci-C 6 )alkyl-0-phenyl,
  • R 2 and R 6 may be the same or different and are independently H, -(Ci-C4)alkyl, -0-(Ci- C 3 )alkyl, -CF 3 , -CN, CI or F;
  • R 3 is optionally substituted phenyl, optionally substituted piperidinyl, optionally substituted furanyl, optionally substituted pyrimidinyl, optionally substituted pyridinyl, optionally substituted (C 3 -C 6 )cycloalkyl, -(CH 2 ) n -R n , -CO-OR 11 , -CO-R 11 , -CON(R 7 )(R n ), - N(R 7 )(R n ), -SOR 11 , -S0 2 R n and optionally substituted straight or branched (Ci-C 8 )alkyl chain.
  • the invention provides a compound according to the fourteenth through sixteenth embodiments wherein R 1 is optionally substituted phenyl, optionally substituted furanyl, optionally substituted indolyl, optionally substituted isoxazolyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolyl, unsubstituted (C 2 -C 5 )alkyl, substituted (d- C 6 )alkyl, -COR 11 , -N(R 7 )(R 8 ), optionally substituted -0-(d-C 3 )alkyl, or optionally substituted (C 3 -C 6 )cycloalkyl;
  • R 2 and R 6 may be the same or different and are independently H, -CF 3 , CI
  • R 3 is optionally substituted phenyl, optionally substituted piperidinyl optionally substituted pyrimidinyl, optionally substituted pyridinyl, optionally substituted (C 3 - C 6 )cycloalkyl, -(CH 2 ) n -R n , optionally substituted straight or branched (Ci-C 8 )alkyl chain or
  • each R 9 is independently selected from H or optionally substituted (Ci-C 6 )alkyl.
  • each substituent or optional substituent is independently one or more R 10 groups wherein R 10 is optionally substituted alkyl, alkenyl, optionally substituted alkoxy groups, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,
  • the invention provides a compound according to fourteenth through nineteenth embodiments wherein -Y-R 3 is
  • R is -3-(( 1&S,5&R)- 1 , 1 ,2-Trimethyl-l , la,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalenyl, or optionally substituted thienyl;
  • R a is H or optionally substituted (Ci-C 6 )alkyl
  • R b is H, optionally substituted (Ci-C 6 )alkyl or optionally substituted (C 3 -C 6 )cycloalkyl.
  • R b is H, optionally substituted (Ci-C 6 )alkyl or optionally substituted (C 3 -C 6 )cycloalkyl.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to any of the foregoing embodiments or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof and a pharmaceutically acceptable diluent or carrier.
  • the invention provides for the use of one or more compounds according to any of the foregoing embodiments or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug or stereoisomer thereof for the manufacture of a medicament for treating an immune disorder.
  • the invention provides for the use according the twenty- fifth embodiment wherein the immune disorder is active chronic hepatitis, Addison's Disease, ankylosing spondylitis, anti-phospholipid syndrome, asthma, atopic allergy, autoimmune atrophic gastritis, achlorhydra autoimmune, Celiac Disease, Crohn's Disease, Cushing's Syndrome, dermatomyositis, Goodpasture's Syndrome, Grave's Disease, Hashimoto's thyroiditis, idiopathic adrenal atrophy, idiopathic thrombocytopenia, juvenile rheumatoid arthritis, Lambert-Eaton Syndrome, lupoid hepatitis, lupus, mixed connective tissue disease, multiple sclerosis, pemphigoid, pemphigus vulgaris, pernicious anemia, phacogenic uveitis, polyarteritis nodosa, primary biliary cirrhosis, primary s
  • the invention provides for the use of one or more compounds according to any of the foregoing embodiments or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof for the manufacture of a medicament for treating a central nervous system disorder.
  • the invention provides for the use of one or more compounds according to any of the foregoing embodiments or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof for the manufacture of a medicament for treating multiple sclerosis.
  • the invention provides for the use of one or more compounds according to claims any of the foregoing embodiments or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof for the manufacture of a medicament for treating rheumatoid arthritis.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds according to Formula (I), (la), (II), (III), (IV), or (V) 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 packaged pharmaceutical comprising a one or more compounds according to Formula (I), (la), (II), (III), (IV), or (V) 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.
  • a “therapeutically effective amount” is an amount of a compound of Formula (I), (II), (III), (IV), or (V) 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 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, 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), (II), (III), (IV), or (V) 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), (II), (III), (IV), or (V), 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), (II), (III), (IV), or (V) 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), (II), (III), (IV), or (V) may contain one or more chiral centers, and exist in different optically active forms.
  • compounds of Formula (I), (II), (III), (IV), or (V) 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), (la), (II), (III), (IV), or (V) 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 enantiomers may be separated as described above.
  • the present invention includes each diastereoisomer of compounds of Formula (I), (la), (II), (III), (IV), or (V) and mixtures thereof.
  • Certain compounds of Formula (I), (la), (II), (III), (IV), and (V) 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), (II), (III), (IV), and (V) and mixtures thereof.
  • Certain compounds of Formula (I), (la), (II), (III), (IV), and (V) 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), (la), (II), (III), (IV), and (V), and mixtures thereof.
  • Certain compounds of Formula (I), (la), (II), (III), (IV), and (V) may exist in zwitterionic form and the present invention includes each zwitterionic form of compounds of Formula (I), (la), (II), (III), (IV), and (V) 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 parent drug. 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 parent drug.
  • 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 intravenous administration of the drug. A prodrug 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(0)OH or a moiety that contains a carboxylic acid) wherein the free hydrogen is replaced by (Ci-C 4 )alkyl, (C 2 -Ci2)alkanoyloxymethyl, (C 4 - C9)l -(alkanoyloxy)ethyl, 1 -methyl- 1 -(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1 -(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)
  • exemplary pro-drugs release an alcohol of Formula (I), (la), (II), (III), (IV), and (V) wherein the free hydrogen of the hydroxyl substituent (e.g., R 1 contains hydroxyl) is replaced by (Ci-C6)alkanoyloxymethyl, l-((Ci-C6)alkanoyloxy)ethyl, l-methyl-l-((Ci-C6)alkanoyloxy)ethyl, (Ci-C6)alkoxycarbonyloxym ethyl, N-(Ci-C6)alkoxycarbonylamino-methyl, succinoyl, (Ci- Ce)alkanoyl, a-amino(Ci-C4)alkanoyl, arylactyl and a-aminoacyl, or a-aminoacyl-a-aminoacyl wherein said a-aminoacyl moieties are independently any of the naturally occurring L-amino
  • 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 azabicyclo[2.2.1]heptanyl, azepinyl, azetidinyl, morpholinyl, oxopiperidinyl, oxopyrrolidinyl, 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.
  • azaindolyl benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4- djpyrimidinyl, quinolin
  • substituted heterocyclic or heterocyclyl
  • substituted heteroaryl or substituted heteroaryl
  • substituted aryl is used, what is meant is that the heterocyclic, heteroaryl or aryl 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, heteroaryl or aryl group of this invention are each independently selected from the optionally substituted group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylheterocycloalkoxy, alkyl, alkylamino, alkylcarbonyl, alkylester, alkyl-NH-alkyl, -alkyl-NH-cycloalkyl, alkyl-O-C(O)-, -alkyl- heterocyclyl, -alkyl-cycloalkyl, alkyl-nitrile, alkynyl, amido groups, amino, aminoalkyl, aminocarbonyl, carbonitrile, carbonylalkoxy, carboxamido, CF 3 , CN, -C(0)OH, -C(0)H, -C(
  • R c for each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted aryl, -(Ci-C 6 )-NR d R e , -E-(CH 2 ) t -NR d R e , -E-(CH 2 ) t -0-alkyl, -E- (CH 2 ) t -S-alkyl, or -E-(CH 2 ) t -OH;
  • t is an integer from about 1 to about 6;
  • Z 105 for each occurrence is independently a covalent bond, alkyl, alkenyl or alkynyl;
  • 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(0) 2 , or NR f , wherein R f is H or alkyl and R d and R e are independently H, alkyl, alkanoyl or S0 2 -alkyl; or R d , 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 about eight carbon atoms.
  • a morpholinomethyl group is an heterocycloalkyl group.
  • aliphatic or “an aliphatic group” or notations such as “(C 0 -C 8 )” 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 Co it means that the moiety is not present or in other words, it is a bond.
  • alkyl means Ci-Cg and includes straight chained or branched hydrocarbons, which are completely saturated.
  • alkyls examples are methyl, ethyl, propyl, butyl, pentyl, hexyl and isomers thereof.
  • alkenyl and alkynyl means C2-C8 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 C3-Q2 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.
  • Examples of a cycloalkyl group are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.
  • alkenyl groups alkoxy group (which itself can be substituted, such as -0-Ci-C 6 -aikyl-OR, -0-Ci-C 6 -alkyl-N(R) 2 , and OCF 3 ), alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylpiperidinyl-alkoxy, alkyl groups (which itself can also be substituted, such as -Ci-C 6 -aikyl-OR, -Ci-C 6 -alkyl-N(R) 2 , COOH, and -CF 3 ), alkylamino, alkylcarbonyl, alkylester, alkylnitrile, alkylsulfonyl, amino, aminoalkoxy, CF3, COH, COOH, CN, cycloalkyl, dialkylamin
  • the present invention provides compounds described by general Formula (I), (la), (II), (III), (IV), and (V), which are effective as antagonists or agonists of the G protein-coupled SIP 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 SIP receptor family.
  • the invention provides a method for modulating receptors of the SIP family in a human subject suffering from a disorder in which modulation of SIP activity is beneficial, comprising administering to the human subject a compound of Formula (I), (la), (II), (III), (IV), and (V) such that modulation of SIP activity in the human subject is triggered and treatment is achieved.
  • the invention provides a method of modulating sphingosine 1- phosphate receptor 1 activity comprising contacting a cell with one or more compounds of Formula (I), (la), (II), (III), (IV), and (V).
  • a compound of Formula (I), (la), (II), (III), (IV), and (V) 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, ankylosing spondylitis, 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'
  • 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), (la), (II), (III), (IV), and (V) of the invention can be used alone or in combination with another therapeutic agent to treat such diseases.
  • the compounds of the invention can be used alone or in combination with an additional agent, e.g., a therapeutic agent, said additional agent being selected by the skilled artisan for its intended purpose.
  • 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 SIP receptor agonists or antagonists of this invention.
  • Non-limiting examples of therapeutic agents for rheumatoid arthritis with which a compound of Formula (I), (la), (II), (III), (IV), and (V), of the invention can be combined include the following: cytokine suppressive antiinflammatory drug(s) (CSAIDs); antibodies to or antagonists of other human cytokines or growth factors, for example, TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF, and PDGF.
  • CSAIDs cytokine suppressive antiinflammatory drug
  • 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 CD 154 (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 CD 154 (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, D2E7 (HUMIRATM), (PCT Publication No. WO 97/29131), CA2 (REMICADETM), CDP 571, and soluble p55 or p75 TNF receptors, derivatives, thereof, (p75TNFRlgG (ENBRELTM) or p55TNFRlgG (Lenercept), and also TNF a converting enzyme (TACE) inhibitors; similarly IL-1 inhibitors (Interleukin-1 -converting enzyme inhibitors, IL-IRA etc.) may be effective for the same reason.
  • TNF antagonists like chimeric, humanized or human TNF antibodies, D2E7 (HUMIRATM), (PCT Publication No. WO 97/29131), CA2 (REMICADETM), CDP 571, and soluble p55 or p75 TNF receptors, derivatives, thereof
  • 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 IL-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), (la), (II), (III), (IV), and (V) 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, NSAIDs, for example, ibuprofen,
  • IL- ⁇ 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)), sIL-lRI, sIL-lRII, sIL-6R), antiinflammatory cytokines (e.g.
  • IL-4, IL-10, IL-11, 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 HC1, hydrocodone bitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra, tramadol HC1, salsalate, sulindac, cyan
  • Non-limiting examples of therapeutic agents for inflammatory bowel disease with which a compound of Formula (I), (la), (II), (III), (IV), or (V) 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-1 receptor antagonists; anti-IL- ⁇ 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, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL
  • IL- ⁇ ⁇ converting enzyme inhibitors include IL- ⁇ ⁇ converting enzyme inhibitors; TNFa converting enzyme inhibitors; T- cell signalling 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. IL-4, IL-10, IL-11, IL-13 and TGF ).
  • TNF antagonists for example, anti- TNF antibodies, D2E7 (PCT Publication No. WO 97/29131 ; HUMIRATM), CA2 (REMICADETM), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBRELTM) and p55TNFRIgG (LenerceptTM)) inhibitors and PDE4 inhibitors.
  • a compound of Formula (I), (la), (II), (III), (IV), or (V) 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 IL-1, for example, IL- ⁇ ⁇ converting enzyme inhibitors and IL-lra; T cell signaling inhibitors, for example, tyrosine kinase inhibitors 6-mercaptopurines; IL-11; mesalamine; prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolone sodium succinate; diphenoxylate/atrop sulfate; loperamide hydrochloride; methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water; hydroco
  • Non-limiting examples of therapeutic agents for multiple sclerosis with which a compound of Formula (I), (la), (II), (III), (IV),or (V) can be combined include the following: corticosteroids; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine; tizanidine; interferon- ia (Avonex®; Biogen); inter feron- ⁇ lb (Betaseron®; Chiron/Berlex); interferon a-n3) (Interferon Sciences/Fujimoto), interferon-a (Alfa Wassermann/J&J), interferon ⁇ -IF (Serono/Inhale Therapeutics), Peginterferon a 2b (Enzon/Schering-Plough), Copolymer 1 (Cop-1; Copaxone®; Teva Pharmaceutical Industries, Inc.); hyperbar
  • a compound of Formula (I), (la), (II), (III), (IV), or (V) can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands.
  • cell surface molecules such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands.
  • a compound of Formula (I), (la), (II), (III), (IV), or (V) 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 a or IL-1 (e.g.
  • IL- ⁇ converting enzyme 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. IL-4, IL-10, IL-13 and TGF ).
  • TACE 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
  • interferon- ⁇ for example, IFN ia and IFNpib
  • Copaxone corticosteroids
  • caspase inhibitors for example inhibitors of caspase- 1, IL-1 inhibitors, TNF inhibitors, and antibodies to CD40 ligand and CD80.
  • a compound of Formula (I), (la), (II), (III), (IV), or (V) may also be combined with agents, such as alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol, a-immunokine NNS03, ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulated mitoxantrone), THC.CBD (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
  • Non-limiting examples of therapeutic agents for angina with which a compound of Formula (I), (la), (II), (III), (IV), or (V) 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 HC1, digoxin, propranolol hydrochloride, carvedilol, lisinopril, spironolactone, hydrochlorothiazide, enalapril maleate, nadolol, ramipril, enoxaparin sodium, heparin sodium, valsartan
  • Non-limiting examples of therapeutic agents for ankylosing spondylitis with which a compound of Formula (I), (la), (II), (III), (IV), or (V) 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), (la), (II), (III), (IV), or (V) can be combined include the following: albuterol, salmeterol/fluticasone, montelukast sodium, fluticasone propionate, budesonide, prednisone, salmeterol xinafoate, levalbuterol HC1, 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, fexof
  • Non-limiting examples of therapeutic agents for COPD with which a compound of Formula (I), (la), (II), (III), (IV), or (V) 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/ment
  • Non-limiting examples of therapeutic agents for HCV with which a compound of Formula (I), (la), (II), (III), (IV), or (V) can be combined include the following: Interferon-alpha- 2a, Interferon-alpha-2b, Interferon-alpha conl, Interferon-alpha-nl, pegylated interferon-alpha-2a, pegylated interferon-alpha-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), (la), (II), (III), (IV), or (V) 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-alpha, methotrexate
  • Non-limiting examples of therapeutic agents for myocardial infarction with which a compound of Formula (I), (la), (II), (III), (IV), or (V) 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 HC1 m-hydrate,
  • Formula (I), (la), (II), (III), (IV), or (V) 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, lactic
  • Non-limiting examples of therapeutic agents for psoriatic arthritis with which a compound of Formula (I), (la), (II), (III), (IV), or (V) 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
  • Non-limiting examples of therapeutic agents for restenosis with which a compound of Formula (I), (la), (II), (III), (IV), or (V) 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), (la), (II), (III), (IV), or (V) 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, nabu
  • Preferred examples of therapeutic agents for SLE (Lupus) with which a compound of Formula (I), (la), (II), (III), (IV), or (V) can be combined include the following: NSAIDS, 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®.
  • NSAIDS for example, diclofenac, naproxen, ibuprofen, piroxicam, indomethaci
  • a compound of Formula (I), (la), (II), (III), (IV), or (V) 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-1, for example, caspase inhibitors like IL- ⁇ ⁇ 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-1, for example, caspase inhibitors like IL- ⁇ ⁇ converting enzyme inhibitors and IL-lra.
  • a compound of Formula (I), (la), (II), (III), (IV), or (V) 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 family antibodies.
  • 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 family antibodies.
  • a compound of Formula (I), (la), (II), (III), (IV), or (V) can be combined with IL-11 or anti-cytokine antibodies, for example, fonotolizumab (anti-IFNg 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), (la), (II), (III), (IV), or (V) 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, D2E7 (PCT Publication No. WO 97/29131; HUMIRATM), CA2 (REMICADETM), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBRELTM) and p55TNFRIgG (LENERCEPTTM)).
  • LJP 394 assay for example, anti-TNF antibodies, D2E7 (PCT Publication No. WO 97/29131; HUMIRATM), CA2 (REMICADETM), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBRELTM) and p55TN
  • 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-1 inhibitors, COX-2 inhibitors, NO synthase inhibitors, Akt/PTB inhibitors, IGF-1R inhibitors, PKC inhibitors, PI3 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.
  • 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.
  • Pharmaceutical preparations 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).
  • 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 For this purpose, concentrated sugar solutions 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, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, 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.
  • compositions 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. Optionally, 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 co-solvent 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.
  • 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.
  • compositions also may comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase 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.
  • 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.
  • 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 5 0 as determined in cellular assays (i.e., the concentration of the test compound which achieves a half- maximal inhibition of a given receptor activity).
  • a concentration range that includes the EC 5 0 as determined in cellular assays (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.
  • advantageous compounds for systemic administration effectively modulate receptors of the SIP 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 5 0 (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 ah, 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 pi).
  • 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 SIP 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%o 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.
  • the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
  • active compound denotes any compound of the invention but particularly any compound which is the final product of one of the preceding Examples.
  • capsules 10 parts by weight of active compound and 240 parts by weight of lactose can be de-aggregated and blended. The mixture can be filled into hard gelatin capsules, each capsule containing a unit dose or part of a unit dose of active compound.
  • 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).
  • 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), (la), (II), (III), (IV), or (V) as a medicament.
  • a further aspect of the present invention provides the use of a compound of Formula (I), (la), (II), (III), (IV), or (V) 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), (la), (II), (III), (IV), or (V) to a mammal, particularly a human being, in need thereof.
  • the [ 35 S]GTPyS binding assay can be run using both scintillation proximity assay (SPA) and filtration methods. Both formats are in 96 well plates and utilize membranes from a stable or transient CHO human cell lines overexpressing SIPi, S1P 3 , S1P 4 or S1P 5 . Compound stocks were made up to 10 mM using DMSO and serial dilutions were carried out using 100%o DMSO. Compounds were transferred to 96 well plates to yield a final DMSO concentration of 1 % for all assays (lul for a 100 ⁇ 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, lOOmM NaCl, 5mM MgCl 2 and ⁇ GDP.
  • assay buffer containing of 20 mM HEPES pH 7.4, 0.1% fatty acid-free BSA, lOOmM NaCl, 5mM MgCl 2 and ⁇ GDP.
  • SPA assay membranes are premixed with WGA-SPA beads to yield a final concentration per well of 5 ⁇ g membrane and 500 ⁇ g of bead.
  • membranes are added directly to the incubation plate at 5ug per well. The assay begins with the addition of 50 ⁇ of the membrane or membrane/bead mixture to each well of the assay plate.
  • Radio ligand binding was carried out using membranes from transiently transfected HEK cells overexpressing SIPi, S1P 3 , S1P 4 or S1P 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]S1P is purchased from Perkin Elmer and used at 50 pM in all assays. Frozen membranes are thawed and resuspended in assay buffer containing 50 mM HEPES pH 7.4, 100 mM NaCl, 10 mM MgCl 2 and 0.1% fatty acid free BSA.
  • Membrane is added to give 5-10 ⁇ g of membrane per well. Non-specific binding is determined in the presence of cold 1 ⁇ SIP. 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 ACN.
  • Mobile phase A was lOmM ammonium acetate, mobile phase B was HPLC grade ACN.
  • the column used for the chromatography is a 4.6x50 mm MAC -MOD Halo CI 8 column (2.7 ⁇ particles).
  • Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive/negative electrospray ionization.
  • DAD diode array
  • ELSD evaporative light scattering
  • mobile phase A was 10 mM ammonium acetate
  • mobile phase B was HPLC grade ACN.
  • Samples were purified by preparative HPLC on a Phenomenex Luna C8(2) 5 um lOOA AXIA column (30mm 75mm). A gradient of ACN (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/min (0-0.5 min 10% A, 0.5-6.0 min linear gradient 10-100% A, 6.0-7.0 min 100% A, 7.0-8.0 min linear gradient 100-10% A). Samples were injected in 1.5mL DMSO:MeOH (1 : 1).
  • chromatography was a 4.6x30 mm Vydac Genesis C8 column (4 mm particles). The gradient was 5-35% B in 4 min then 35-95% B to 6 min with a hold at 95% B for 1.7 min (1.3 mL/min flow rate).
  • Mobile phase A was 10 mM ammonium acetate
  • mobile phase B was HPLC grade ACN.
  • Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as pos/neg electrospray ionization.
  • chromatography was a 4.6x30 mm Vydac Genesis C8 column (4 mm particles). The gradient was 30-95% B in 2 min then hold at 95% B to 5.7 min (1.3 mL/min flow rate).
  • Mobile phase A was 10 mM ammonium acetate
  • mobile phase B was HPLC grade ACN.
  • Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as pos/neg electrospray ionization.
  • mobile phase A was 10 mM ammonium acetate
  • mobile phase B was HPLC grade ACN.
  • the final compounds may be purified by any technique or combination of techniques known to one skilled in the art.
  • Some examples that are not limiting include flash chromatography with a solid phase (e.g. silica gel, alumina, etc.) and a solvent (or combination of solvents) that elutes the desired compounds (e.g. heptane, EtOAc, DCM, MeOH, MeCN, water, etc.); preparatory TLC with a solid phase (e.g. silica gel, alumina etc.) and a solvent (or combination of solvents) that elutes the desired compounds (e.g.
  • MeOH, EtOH, IPA with or without additional modifier such as diethylamine, TFA, etc.
  • precipitation from a combination of solvents e.g. DMF/water, DMSO/DCM, EtO Ac/heptane, etc.
  • trituration with an appropriate solvent e.g. EtOAc, DCM, MeCN, MeOH, EtOH, IPA, «- ⁇ , etc.
  • extractions by dissolving a compound in a liquid and washing with an appropriately immiscible liquid e.g.
  • step i a suitably substituted nitrile compound 1 (commercially available or made through General procedure A or B) is reacted with hydroxylamine to give compound 2.
  • a protic solvent such as MeOH or EtOH
  • reflux such as 60 °C
  • the product 2 is typically isolated from the reaction mixture as a solid by concentrating the mixture. Compound 2 can be used as it is.
  • step ii Coupling of compound 2 with a suitable acid or acid chloride followed by ring closure to produce compound 3 is shown in step ii.
  • the coupling reaction is typically carried out with carboxylic acids in the presence of a coupling reagent (such as HOBt, DCC) or with acid chlorides in the presence of an organic base (such as DIEA, Et 3 N) at room temperature or elevated temperature (for example, 20 - 180 °C) in a solvent such as DMF or DMA.
  • the subsequent ring closure reaction is complete in situ at elevated temperature (for example 160 °C) (see, for example, Wang, et ah, Org Lett 2005 7(5), 925 - 928).
  • the compounds 3 can then be isolated and purified using standard techniques (such as reverse- phase liquid chromatography or SFC).
  • Example A.33 4-[3-(3-chloro-4-isopropoxy-phenyl)-[l,2,4]oxadiazol-5-yl]-pyridine was prepared from 3-chloro-A ⁇ -hydroxy-4-isopropoxy-benzamidine using general procedure D, as represented in the following synthetic scheme:
  • Example A.33 3-chloro-Af-hydroxy-4-isopropoxy-benzamidine was prepared using the route (A, C). This translates into the following synthetic sequence, where the hydroxyamidine starting material used in general procedure D is the product by the following the procedure A and C, in the given order.
  • Triphenylphosphine (1 - 3 equivalents, preferably 1.6 equivalents) and 4-hydroxy-benzonitrile (1 - 3 equivalents, preferably 1 equivalent) are dissolved in an anhydrous organic solvent such as dichloromethane, toluene, or tetrahydrofuran (preferably tetrahydrofuran) under an atmosphere of nitrogen.
  • anhydrous organic solvent such as dichloromethane, toluene, or tetrahydrofuran (preferably tetrahydrofuran) under an atmosphere of nitrogen.
  • an azodicarboxylate such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, or di-teri-butyl azodicarboxylate (preferably di-teri-butyl azodicarboxylate) (1 - 3 equivalents, preferably 1.6 equivalents) is added to the solution and the mixture is stirred for a few minutes before addition of an anhydrous alcohol (1 - 3 equivalents, preferably 1.25 equivalents).
  • the reaction mixture is stirred at 0 - 100 °C (preferably about 23 °C) under an atmosphere of nitrogen for a period of about 2 - 24 hours (preferably 16 hours).
  • the solvent is removed under reduced pressure.
  • the crude product can be further purified by flash column chromatography.
  • a hydroxyamidine (0.9 - 1.5 equivalents, preferably 1.1 equivalent), an acid (0.9 - 1.5 equivalents, preferably 1 equivalent), a coupling reagent such as HBTU, HATU, HOBt, or polymer-bound HOBt (preferably HOBt) (1 - 2 equivalents, preferably 1 equivalent), a carbodiimide such as PS, EDCI, DIC, DCC or polymer-bound DCC (preferably polymer-bound DCC) (1.5 - 3 equivalents, preferably 3 equivalents), a base such as diisopropylethylamine, triethylamine, or N-methylmorpholine (preferably diisopropylamine) (1 - 3 equivalents, preferably 3 equivalents) and a suitable solvent such as DMF, DMA, or ACN (preferably ACN).
  • a coupling reagent such as HBTU, HATU, HOBt, or polymer-bound HOBt (preferably HOBt) (1 - 2 equivalents, preferably 1 equivalent
  • the reaction vial is capped and heated (conventional heating or microwave heating, preferably microwave heating) at 100 - 200 °C (preferably 160 °C) for a period of 15 - 45 min (preferably 30 min).
  • microwave heating preferably microwave heating
  • the crude reaction mixture is filtered, washed with a suitable solvent such as DMF, DMA, or ACN (preferably ACN), and the filtrate is concentrated to dryness under reduced pressure.
  • the crude product is further purified by chromatography.
  • a chlorinating reagent such as thionyl chloride or oxalyl chloride (preferably thionyl chloride) (1 - 100 equivalents, preferably 3 equivalents).
  • thionyl chloride or oxalyl chloride preferably thionyl chloride
  • the reaction mixture is stirred at 20 - 80 °C (preferably at about 23 °C) for a period of 1 - 24 hours (preferably 3 hours).
  • the solvent is removed under reduced pressure.
  • the crude product is dried under vacuum and then subjected to General Procedure E.
  • a mixture of a nitrile in a round bottom flask containing (0.9 - 1.2 equivalents, preferably 1.0 equivalents) in a suitable solvent such as dichloromethane or dichloroethane (preferably dichloromethane) was cooled to between 0 °C and -60 °C (preferably -40 °C).
  • a solution of Dibal-H (0.9 - 2.5 equivalents, preferably 2.0 equivalents) was added dropwise and then the solution was stirred for 15 - 240 minutes (preferably 120 minutes), quenched with methanol, warmed to ambient temperature and treated with a 10% solution of Rochelle's salt. After extraction with DCM the combined organic layers were stirred with dilute aqueous acid (preferably 1M aqueous HC1).
  • the layers were separated and the aqueous layer extracted with DCM.
  • the combined organic layers were washed with brine, dried over MgS0 4 or Na 2 S0 4 , filtered and evaporated to dryness.
  • the crude product is further purified by chromatography.
  • a suitable reducing agent such as polymer supported sodium cyanoborohydride or sodium cyanoborohydride (preferably polymer supported sodium cyanoborohydride )(1.5 - 3.0 equivalents, preferably 2.0 equivalents)
  • acetic acid (2 - 24 drops, preferably 6 drops
  • a suitable solvent such as DCM or methanol (preferably D
  • the material was dissolved in THF (80 mL). To this was added NaOH (9.0 mL, 9.00 mmol) as IN solution, followed by MeOH (about 25 mL). The reaction was stirred at ambient temperature for about 3 h, after which the LC/MS showed that hydrolysis was complete. To the reaction mixture was added HCl (9.0 mL, 9.00 mmol) as IN solution dropwise to neutralize the pH. The reaction mixture was concentrated in vacuo then lyophilized to dryness. The crude white solid was triturated in diethyl ether and DCM then filtered.
  • reaction vial is capped and heated either via microwave with cooling or in an oil bath (preferably via microwave) at 110 - 200 °C (preferably 160 °C) for 15 min to 4 days (preferably 30 min).
  • the crude product is optionally isolated from the reaction mixture by dilution with water followed by filtration or neutralization to pH ⁇ 3 and extraction with a suitable organic solvent (ethyl acetate, dichloromethane, diethyl ether - preferably dichloromethane).
  • a suitable organic solvent ethyl acetate, dichloromethane, diethyl ether - preferably dichloromethane.
  • the product can be further purified by chromatography or crystallization.
  • a phenol such as benzyl 4-hydroxybenzoate (0.9 - 1.2 equivalents, preferably 1 equivalents) and a suitable base (such as potassium carbonate (1 - 5 equivalents, preferably 5 equivalents)) in an organic solvent (such as acetone (about 100 mL)) were combined.
  • the solution was stirred at about 60 - 70°C, preferably about 65°C for 12-24 h, preferably about 18 h.
  • the solution was cooled and the reaction mixture was filtered through a sintered glass funnel. The filtrate was concentrated in vacuo to afford a crude product which can be further purified via chromatography or crystallization.
  • a high-pressure flask was charged with 5-20% (preferably 10%o) palladium on carbon (0.9 - 1.2 equivalents, preferably 1.0 equivalents), a suitable solvent such as MeOH (200 mL), then a benzoate ester (50 - 70 equivalents, preferably 60 equivalents) were added.
  • the resulting suspension was allowed to shake under an atmosphere of hydrogen about 10-70 psi (preferably 47 psi) at ambient temperature for about 2 h.
  • the mixture was filtered through Celite ® and the colorless filtrate was concentrated to afford the product.
  • a solution of an aryl fluoride in a dry, aprotic solvent such as DMF, THF, toluene or 1 ,4-dioxane (preferably THF) is treated with a base such as sodium hydride (1.0 to 3.0 equivalents, preferably about 1.1 equivalents) at 0 - 50 °C (preferably RT).
  • a base such as sodium hydride (1.0 to 3.0 equivalents, preferably about 1.1 equivalents) at 0 - 50 °C (preferably RT).
  • the mixture is treated dropwise with a solution of an alcohol (1-10 equivalents, preferably 1.0 - 1.1 equivalents) and then the reaction is stirred at 20 - 150° C (preferably about 40°C) until the aryl fluoride is consumed.
  • the reaction is then cooled and concentrated then purified by extractive workup, crystallization or chromatography.
  • the crude material may be deprotected by hydrolysis during the extractive workup.
  • a solution of an ester in an organic solvent such as THF, MeOH, 1 ,4-dioxane, methanol, ethanol, DMF or DMSO (preferably THF, MeOH or 1,4-dioxane) is treated with an aqueous base (1-10 equivalents, preferably about 1 equivalent) such as NaOH, LiOH or KOH and the mixture is stirred at 20 - 100 °C (preferably RT) until the reaction is complete.
  • the reaction is neutralized with an acid such as HC1, H 2 S0 4 , or acetic acid (preferably HC1), cooled, concentrated and purified by extractive workup, crystallization or chromatography.
  • Methyl 5-chloro-6-hydroxynicotinate (3.86 g) was dissolved in about 21 mL methanol and about 2.1 mL water was added. 1.74 g sodium hydroxide was added to the solution. The mixture was heated to about 50° C and mixed well to dissolve all NaOH and the solution was stirred for about 1 h at the same temperature. The aqueous methanol solution was extracted with hexane (2X10 mL) and the aqueous layer was adjusted to pH 4 using 6N HC1. Methanol was then removed by concentration and the aqueous slurry was adjusted to pH ⁇ l using HC1 in an ice bath. The resulting slurry was stirred for about 30 min then filtered and washed with water. The product was further purified by drying under vacuum. Yield 3.64 g. HPLC purity 98%, 9.404 min. HPLC (Table 1, Method q) General Procedure R: Mitsunobu coupling to a phenol
  • a solution of a phenol and alcohol (1-3 equivalents, preferably about 1.1 equivalents) in a solvent such as THF or 1,4-dioxane (preferably THF) is treated with a phosphine (1-5 equivalents) such as triphenylphosphine or resin-bound triphenylphosphine (preferably resin-bound triphenylphosphine) and optionally with 4A molecular sieves and the mixture is cooled to about 0 °C.
  • a solution of an alkylazodicarboxylate such as diethylazodicarboxylate, diisopropylazodicarboxylate, or di-teri-butylazodicarboxylate (preferably di-teri-butylazodicarboxylate) in a solvent such as THF or 1,4-dioxane (preferably THF) is added dropwise and then the reaction is warmed to 20-70 °C (preferably RT) with stirring for 1-24 h (preferably about 18 h). The reaction is filtered, concentrated and purified by chromatography on silica gel or crystallization.
  • a solvent such as THF or 1,4-dioxane (preferably THF)
  • a suspension of 1-3 equivalents sodium hydride (60%o in mineral oil, preferably 1.6 equivalent) in about 5 mL DMSO was heated at about 80-100 °C (preferably about 80 °C) for about 15-30 min (preferably 15 min).
  • the mixture was cooled down to about 0-5 °C in an ice-bath, (4-(3-(3- chloro-4-isopropoxyphenyl)- 1 ,2,4-oxadiazol-5 -yl)benzyl)triphenylphosphonium chloride (preferably 1 equivalent) was added in one portion, the reaction mixture was stirred at RT for 30 min.
  • a solution of ketone (preferably 1.2 equivalents) in DMSO was added dropwise.
  • the reaction mixture was heated at about 80 °C for about 12-120 h (preferably 64 h). After cooling down, the mixture was poured into ice water, acidified by HC1 (6N), extracted by DCM or ethyl acetate, the organic layer was washed by HC1 (IN) and brine, dried over magnesium sulfate, filtration and concentration afford a crude product, which is further purified by chromatography.
  • a high-pressure flask was charged with a benzylic olefin (1 equivalent) and palladium on carbon (preferably 0.25 equivalents in ethyl acetate). The resulting suspension was stirred under an atmosphere of hydrogen (14 Psi) at ambient temperature for about 30-90 minutes (preferably 60 minutes). The mixture was filtered through Celite ® and the colorless filtrate was concentrated to afford the product.
  • a solution of ester (1 equivalent) in ethyl alcohol/l,4-dioxane or toluene is combined with a solution of potassium/sodium hydroxide or Ag 2 C0 3 (1-10 equivalents, preferably 10 equivalent) in water, the mixture is heated at about 60-100 °C for about 16-20 hours.
  • the reaction mixture is cooled down, and the resulting crude product mixture can be further purified by extractive workup and/or chromatography .
  • Methyl 5-chloro-6-hydroxynicotinate (8.91 g, 47.5 mmol) and 2-iodo-propane (7.12 mL, 71.2 mmol) were combined in toluene (202 mL) under nitrogen to give a colorless solution.
  • Silver carbonate (19.65 g, 71.2 mmol) was added and the reaction heated at about 60 °C for about 4 h.
  • TLC in 1 : 1 EtO Ac/heptane showed (uv light visualization) that the reaction was not yet complete. The temperature was reduced to about 50 °C and the reaction stirred for about an additional 16 h. The reaction was allowed to cool to ambient temperature.
  • nitrile precursors The letter in parentheses below the nitrile precursors indicates the General Procedure by which the nitrile precursor was made.

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Abstract

La présente invention concerne des composés inédits d'oxadiazole, des compositions pharmaceutiques contenant lesdits composés et l'utilisation de ces composés ou compositions en tant qu'agonistes ou antagonistes de la famille S1P des récepteurs couplés aux protéines G, en vue du traitement de maladies associées à la modulation de l'activité des récepteurs de la famille S1P, grâce, en particulier, à leur intéressant effet immunosuppresseur.
PCT/US2010/046424 2009-12-08 2010-08-24 Composés inédits d'oxadiazole WO2011071570A1 (fr)

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CA2783851A CA2783851A1 (fr) 2009-12-08 2010-08-24 Composes inedits d'oxadiazole
EP10836346.6A EP2509424A4 (fr) 2009-12-08 2010-08-24 Composés inédits d'oxadiazole
JP2012543093A JP2013512951A (ja) 2009-12-08 2010-08-24 新規オキサジアゾール化合物
MX2012006667A MX2012006667A (es) 2009-12-08 2010-08-24 Compuesto de oxadiazol novedosos.
CN2010800633803A CN102762102A (zh) 2009-12-08 2010-08-24 新的噁二唑化合物

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WO2013036530A1 (fr) 2011-09-08 2013-03-14 Allergan, Inc. Modulateurs de récepteurs de 3-(4-(5-phényl-1,2,4-oxadiazol-3-yl)phénoxy)propan-2-ol en tant que modulateurs de récepteurs de sphingosine-1-phosphate
US8435999B2 (en) 2007-08-13 2013-05-07 Monsanto Technology Llc Compositions and methods for controlling nematodes
US9617250B2 (en) 2013-03-15 2017-04-11 Actelion Pharmaceuticals Ltd. Pyridin-4-yl derivatives
EP3160949A4 (fr) * 2014-06-26 2018-01-17 Monash University Agents d'interaction avec des enzymes
CN109369620A (zh) * 2018-12-22 2019-02-22 山东大学 吡啶类化合物及其制备方法与抗胃癌应用
CN109776443A (zh) * 2019-03-25 2019-05-21 河南湾流生物科技有限公司 一种具有抗氧化作用的噁二唑类化合物及其制备方法
WO2020060915A1 (fr) * 2018-09-18 2020-03-26 Bristol-Myers Squibb Company Acides cyclopentyliques utilisés comme antagonistes de lpa
WO2020060916A1 (fr) * 2018-09-18 2020-03-26 Bristol-Myers Squibb Company Acides cycloheptyliques utilisés comme antagonistes de lpa
WO2021099518A1 (fr) 2019-11-19 2021-05-27 Modag Gmbh Nouveaux composés pour le diagnostic, le traitement et la prévention de maladies associées à l'agrégation de l'alpha-synucléine
CN113662938A (zh) * 2021-09-26 2021-11-19 广西科技大学 一种胺类衍生物在制备抗肿瘤药物组合物中的应用
US11427586B2 (en) 2019-11-25 2022-08-30 Novartis Ag 1,2,4-oxadiazole derivatives as liver X receptor agonists
WO2023118253A1 (fr) * 2021-12-23 2023-06-29 Chiesi Farmaceutici S.P.A. Dérivés d'acide cyclohexane utilisés en tant qu'inhibiteurs du récepteur de lpa

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CN115260173A (zh) * 2021-04-30 2022-11-01 厦门宝太生物科技股份有限公司 环戊烷并吲哚类支链酸衍生物及其制备方法和应用
CN116444454B (zh) * 2023-06-16 2023-09-12 中国医学科学院医药生物技术研究所 N-羟基脒衍生物及制备方法和应用、肿瘤免疫治疗药物

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9642364B2 (en) 2007-08-13 2017-05-09 Monsanto Technology Llc Compositions and methods for controlling nematodes
US10827753B2 (en) 2007-08-13 2020-11-10 Monsanto Technology Llc Compositions and methods for controlling nematodes
US10375958B2 (en) 2007-08-13 2019-08-13 Monsanto Technology Llc Compositions and methods for controlling nematodes
US9125410B2 (en) 2007-08-13 2015-09-08 Monsanto Technology Llc Compositions and methods for controlling nematodes
US9420788B2 (en) 2007-08-13 2016-08-23 Monsanto Technology Llc Compositions and methods for controlling nematodes
US10112930B2 (en) 2007-08-13 2018-10-30 Monsanto Technology Llc Compositions and methods for controlling nematodes
US8435999B2 (en) 2007-08-13 2013-05-07 Monsanto Technology Llc Compositions and methods for controlling nematodes
WO2013036530A1 (fr) 2011-09-08 2013-03-14 Allergan, Inc. Modulateurs de récepteurs de 3-(4-(5-phényl-1,2,4-oxadiazol-3-yl)phénoxy)propan-2-ol en tant que modulateurs de récepteurs de sphingosine-1-phosphate
US8729109B2 (en) 2011-09-08 2014-05-20 Allergan, Inc. 3-(4-(5-phenyl-1 ,2,4-oxadiazol-3-yl)phenoxy)propan-2-ol derivatives as sphingosine-1phosphate receptors modulators
US9617250B2 (en) 2013-03-15 2017-04-11 Actelion Pharmaceuticals Ltd. Pyridin-4-yl derivatives
EP3160949A4 (fr) * 2014-06-26 2018-01-17 Monash University Agents d'interaction avec des enzymes
WO2020060915A1 (fr) * 2018-09-18 2020-03-26 Bristol-Myers Squibb Company Acides cyclopentyliques utilisés comme antagonistes de lpa
WO2020060916A1 (fr) * 2018-09-18 2020-03-26 Bristol-Myers Squibb Company Acides cycloheptyliques utilisés comme antagonistes de lpa
CN109369620A (zh) * 2018-12-22 2019-02-22 山东大学 吡啶类化合物及其制备方法与抗胃癌应用
CN109776443A (zh) * 2019-03-25 2019-05-21 河南湾流生物科技有限公司 一种具有抗氧化作用的噁二唑类化合物及其制备方法
CN109776443B (zh) * 2019-03-25 2022-09-27 上海万巷制药有限公司 一种具有抗氧化作用的噁二唑类化合物及其制备方法
WO2021099518A1 (fr) 2019-11-19 2021-05-27 Modag Gmbh Nouveaux composés pour le diagnostic, le traitement et la prévention de maladies associées à l'agrégation de l'alpha-synucléine
EP4368184A2 (fr) 2019-11-19 2024-05-15 Modag GmbH Nouveaux composés pour le diagnostic, le traitement et la prévention de maladies associées à l'agrégation de l'alpha-synucléine
US11427586B2 (en) 2019-11-25 2022-08-30 Novartis Ag 1,2,4-oxadiazole derivatives as liver X receptor agonists
CN113662938A (zh) * 2021-09-26 2021-11-19 广西科技大学 一种胺类衍生物在制备抗肿瘤药物组合物中的应用
WO2023118253A1 (fr) * 2021-12-23 2023-06-29 Chiesi Farmaceutici S.P.A. Dérivés d'acide cyclohexane utilisés en tant qu'inhibiteurs du récepteur de lpa

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