- S1P1 AGONIST AND APPLICATION THEREOF
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The present invention relates to a class of tricyclic compounds and an application thereof as a sphingosine 1-phosphate type 1 (S1P1) receptor agonist. The invention specifically relates to a compound represented by formula (II), and a tautomer and pharmaceutically acceptable salt of same.
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Paragraph 0356; 0359-0361; 0365; 0369-0371
(2021/10/02)
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- Carboxylic acid compound containing diphenyl oxadiazole, and preparation method and medical application of compound
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The invention relates to the field of medicinal chemistry, and particularly relates to a carboxylic acid compound (I) containing a diphenyl oxadiazole skeleton, a preparation method and pharmaceuticalpreparation of the compound, and a use of the compound
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- THIADIAZOLE MODULATORS OF S1P AND METHODS OF MAKING AND USING
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The invention is directed to compounds of the formula: wherein each of the variables are defined herein, as well as methods of making and using the compounds as agonists of S1P1 and/or S1P5 for instance treating an autoimmune disease.
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Paragraph 0277
(2017/01/26)
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- OXADIAZOLE MODULATORS OF S1P METHODS OF MAKING AND USING
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The invention is directed to Compounds of Formula (I): wherein each variable is defined herein, as well as methods of making and using the compounds as agonists of S1P1 and/or S1P5 for instance for treating graft versus host disease and autoimmune diseases.
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Paragraph 0153
(2017/01/23)
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- SELECTIVE SPHINGOSINE 1 PHOSPHATE RECEPTOR MODULATORS AND COMBINATION THERAPY THEREWITH
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Compounds that selectively modulate the sphingosine 1 phosphate receptor are provided, including compounds which modulate subtype 1 of the S1P receptor, and methods of their therapeutic and/or prophylactic use in combination with at least one other medicament adapted for treatement of a malcondition for which activation of S1P1 is medically indicated, such as multiple sclerosis.
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Page/Page column 106; 107
(2015/05/19)
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- Optimization of sphingosine-1-phosphate-1 receptor agonists: Effects of acidic, basic, and zwitterionic chemotypes on pharmacokinetic and pharmacodynamic profiles
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The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients results from the action of its phosphate metabolite on sphingosine-1-phosphate S1P1 receptors, while a variety of side effects have been ascribed to its S1P3 receptor activity. Although S1P and phospho-fingolimod share the same structural elements of a zwitterionic headgroup and lipophilic tail, a variety of chemotypes have been found to show S1P1 receptor agonism. Here we describe a study of the tolerance of the S1P1 and S1P3 receptors toward bicyclic heterocycles of systematically varied shape and connectivity incorporating acidic, basic, or zwitterionic headgroups. We compare their physicochemical properties, their performance in in vitro and in vivo pharmacokinetic models, and their efficacy in peripheral lymphocyte lowering. The campaign resulted in the identification of several potent S1P1 receptor agonists with good selectivity vs S1P3 receptors, efficacy at 1 mg/kg oral doses, and developability properties suitable for progression into preclinical development.
- Skidmore, John,Heer, Jag,Johnson, Christopher N.,Norton, David,Redshaw, Sally,Sweeting, Jennifer,Hurst, David,Cridland, Andrew,Vesey, David,Wall, Ian,Ahmed, Mahmood,Rivers, Dean,Myatt, James,Giblin, Gerard,Philpott, Karen,Kumar, Umesh,Stevens, Alexander,Bit, Rino A.,Haynes, Andrea,Taylor, Simon,Watson, Robert,Witherington, Jason,Demont, Emmanuel,Heightman, Tom D.
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supporting information
p. 10424 - 10442
(2015/02/19)
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- OXADIAZOLE SUBSTITUTED INDAZOLE DERIVATIVES FOR USE AS SPHINGOSINE 1-PHOSPHATE 1 (S1P1) RECEPTOR AGONISTS
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Oxadiazole substituted indazole derivatives of formula (I) or pharmaceutical salts thereof having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their uses in the treatment of various disorders mediated by S1P1 receptors are disclosed.
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Page/Page column 19
(2012/11/13)
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- MORPHOLINE-SPIROCYCLIC PIPERIDINE AMIDES AS MODULATORS OF ION CHANNELS
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The invention relates to morpholine spirocyclic piperidine amide compounds useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.
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- OXADIAZOLE SUBSTITUTED INDAZOLE DERIVATIVES FOR USE AS SPHINGOSINE 1-PHOSPHATE 1 (S1P1) RECEPTOR AGONISTS
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Oxadiazole substituted indazole derivatives of formula (I) or pharmaceutical salts thereof having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their uses in the treatment of various disorders mediated by S1P1 receptor are disclosed.
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Page/Page column 16; 29
(2011/07/07)
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- NOVEL OXADIAZOLE COMPOUNDS
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Novel oxadiazole compounds, pharmaceutical compositions containing such compounds and the use of those compounds or compositions as agonists or antagonists of the S1P family of G protein-coupled receptors for treating diseases associated with modulation o
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- Discovery and development of an efficient, scalable, and robust route to the novel CENP-E inhibitor GSK923295A
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The discovery and development of an efficient manufacturing route to the CENP-E inhibitor 3-chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)- 1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl} -4-[(1-methylethyl)oxy]benzamide (GSK923295A) is described. The existing route to GSK923295A was expensive, nonrobust, used nonideal reagents, and consistently struggled to deliver the API needed for clinical studies. The new synthesis commences from the readily available l-phenylalaninol, which is smoothly converted through to GSK923295A using key Friedel-Crafts acylation as well as selective acylation chemistries. Downstream chemistry to GSK923295A is both high yielding and robust, and the resulting process has been demonstrated first on the kilo scale and subsequently in the pilot plant where 55 kg was successfully prepared. The resulting process is simple, uses cheaper raw materials, is greener in that it avoids using aluminum, tin, and bromination chemistries, and obviates the need for chromatographic purification. Also discussed are the route derived impurities, how they were unambiguously prepared to confirm structure and processing amendments to control their formation, and enhancements to the new process to facilitate future processing.
- Bellingham, Richard,Buswell, A. Mark,Choudary, Bernie M.,Gordon, Andrew H.,Moore, Steve O.,Peterson, Matthew,Sasse, Mike,Shamji, Amin,Urquhart, Michael W. J.
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p. 1254 - 1263
(2011/04/24)
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- COMPOUNDS
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The present invention relates to novel oxadiazole derivatives having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders.
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Page/Page column 14
(2010/07/10)
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- COMPOUNDS
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The present invention relates to novel oxadiazole derivatives having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders.
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Page/Page column 23
(2010/03/02)
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- COMPOUNDS
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The present invention discloses novel compounds having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders.
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Page/Page column 37-38
(2010/12/31)
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- S1P RECEPTORS MODULATORS
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The invention relates to novel compounds that have S1P receptor modulating activity and, preferably, apoptotic activity and/or anti proliferative activity against cancer cells and other cell types. Further, the invention relates to a pharmaceutical comprising at least one compound of the invention for the treatment of diseases and/or conditions caused by or associated with inappropriate S1P receptor modulating activity or expression, for example, cancer. A further aspect of the invention relates to the use of a pharmaceutical comprising at least one compound of the invention for the manufacture of a medicament for the treatment of diseases and/or conditions caused by or associated with inappropriate S1P receptor modulating activity or expression such as cancer.
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Page/Page column 119
(2010/04/30)
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- COMPOUNDS
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The present invention relates to novel oxadiazole derivatives having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders.
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- OXADIAZOLE DERIVATIVES ACTIVE ON SPHINGOSINE-1-PHOSPHATE (SIP)
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The present application discloses oxadiazole based compounds of Formula (I) active on sphingosine-1-phosphate (S1P) in particular useful to treat lupus erythematosus. A is phenyl or a 5 or 6-membered heteroaryl ring; R1 is up to two substituent
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Page/Page column 31-32
(2009/07/25)
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- COMPOUNDS
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The present invention relates to novel oxadiazole derivatives having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders.
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Page/Page column 49-50
(2010/01/12)
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- OXADIAZOLE SUBSTITUTED INDAZOLE DERIVATIVES FOR USE AS SPHINGOSINE 1-PHOSPHATE (S1P) AGONISTS
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The present invention provides compounds of formula (I) or salts thereof, having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders mediated by S1P1 receptors.
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Page/Page column 35
(2008/12/08)
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- OXADIAZOLE DERIVATIVES AS S1P1 RECEPTOR AGONISTS
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The present invention relates to novel oxadiazole compounds of formula (I) having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders.
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Page/Page column 28
(2008/12/06)
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- INDOLE DERIVATIVES AS S1P1 RECEPTOR AGONISTS
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The invention relates to compounds of formula (I) wherein one of R5 and R6 is hydrogen or R2 and the other is (a) processes for their preparation, pharmaceutical compositions containing them and their use in the treatment
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Page/Page column 33
(2008/12/06)
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- NOVEL OXADIAZOLE COMPOUNDS
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Novel oxadiazole compounds, pharmaceutical compositions containing such compounds and the use of those compounds or compositions as agonists or antagonists of the S1P family of G protein-coupled receptors for treating diseases associated with modulation o
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Page/Page column 93-94
(2008/12/06)
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- CERTAIN CHEMICAL ENTITIES, COMPOSITIONS, AND METHODS
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Compounds useful for treating cellular proliferative diseases and disorders by modulating the activity of one or more mitotic kinesins are disclosed.
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Page/Page column 51
(2010/11/27)
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- CERTAIN CHEMICAL ENTITIES, COMPOSITIONS, AND METHODS
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Compounds useful for treating cellular proliferative diseases and disorders by modulating the activity of one or more mitotic kinesins are disclosed.
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Page/Page column 53-54
(2010/11/27)
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- 2-(ARYL)AZACYCLYLMETHYL CARBOXYLATES, SULFONATES, PHOSPHONATES, PHOSPHINATES AND HETEROCYCLES AS S1P RECEPTOR AGONISTS
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The present invention encompasses compounds of Formula I: as well as the pharmaceutically acceptable salts thereof. The compounds are S1P1/Edg1 receptor agonists and thus have immunosuppressive, anti-inflammatory and hemostatic activities by mo
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Page/Page column 49
(2008/06/13)
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- (3,4-DISUBSTITUTED)PROPANOIC CARBOXYLATES AS S1P (EDG) RECEPTOR AGONISTS
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The present invention encompasses compounds of Formula A: A as well as the pharmaceutically acceptable salts thereof. The compounds are S1P1/Edg1 receptor agonists and thus have immunosuppressive, anti-inflammatory and hemostatic activities by modulating leukocyte trafficking, sequestering lymphocytes in secondary lymphoid tissues, and enhancing vascular integrity. The invention is also directed to pharmaceutical compositions containing such compounds and methods of treatment or prevention.
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Page/Page column 47
(2008/06/13)
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- Tetrahydronaphthyridinyl-carboxamides having anti-convulsant activity
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Compounds of formula (I) and pharmaceutically acceptable salts and solvates: where R1is hydrogen, C1-6alkyl (optionally substituted by hydroxy or C1-4alkoxy), phenyl-C1-4alkyl-, C1-6alkenyl, C1-6
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- Substituted isoquinoline derivatives and their use as anticonvulsivants
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This invention relates to novel substituted isoquinoline derivatives and their use as anticonvulsants.
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- Anti-convulsant isoquinolyl-benzamide derivatives
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Compounds of formula (I) and pharmaceutically acceptable salts thereof, where R1is hydrogen, C1-6alkyl (optionally substituted by hydroxy or C1-4alkoxy), C1-6alkenyl, C1-6alkynyl, C1-6alkylCO—, formyl, CF3CO— or C1-6alkylSO2—; R2is hydrogen or up to three substituents selected from halogen, NO2, CN, N3, CF3O—, CF3S—, CF3CO—, trifluoromethyldiazirinyl, C 1-6?alkyl, C1-6alkenyl, C1-6alkynyl, C1-6perfluoroalkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl-, C1-6alkylO—, C1-6alkylCO—, C3-6cycloalkylO—, C3-6cycloalkylCO—, C3-6cycloalkyl-C1-4alkylO—, C3-6cycloalkyl-C1-4alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C1-4alkyl-, C1-6alkylS—, C1-6alkylSO2—, (C1-4alkyl)2NSO2—, (C1-4alkyl)NHSO2—, (C1-4alkyl)2NCO—, (C1-4alkyl)NHCO— or CONH2; or —NR5R6where R5is hydrogen or C1-4alkyl, and R6is hydrogen, C1-4alkyl, formyl, —CO2C1-4alkyl or —COC1-4alkyl; or two R2groups together form a carbocyclic ring that is saturated or unsaturated and unsubstituted or substituted by —OH or ═O; and the two R3groups and the two R4groups are each independently hydrogen or C1-6alkyl or the two R3groups and/or the two R4groups together form a C3-6spiroalkyl group provided that at least one R3and R4group is not hydrogen, are useful in the treatment and prophylaxis of epilepsy and other disorders.
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