- COMPOUNDS AND USES THEREOF
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The present invention features compounds useful in the treatment of neurological disorders and primary brain cancer. The compounds of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing neurological disorders and primary brain cancer.
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- Synthesis, evaluation and metabolic studies of radiotracers containing a 4-(4-[18F]-fluorobenzyl)piperidin-1-yl moiety for the PET imaging of NR2B NMDA receptors
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In this study, novel specific PET radioligands containing the 4-(4-fluorobenzyl)piperidine moiety and selectively antagonistic for the NR2B subunit containing NMDA receptors were developed. Two antagonists, RGH-896 (1a) and 4-(4-fluorobenzyl)piperidinyl-1
- Labas, Romain,Gilbert, Gwéna?lle,Nicole, Olivier,Dhilly, Martine,Abbas, Ahmed,Tirel, Olivier,Buisson, Alain,Henry, Jo?l,Barré, Louisa,Debruyne, Danièle,Sobrio, Franck
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p. 2295 - 2309
(2011/06/21)
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- Piperidine-based heterocyclic oxalyl amides as potent p38α MAP kinase inhibitors
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The design and synthesis of a new class of p38α MAP kinase inhibitors based on 4-fluorobenzylpiperidine heterocyclic oxalyl amides are described. Many of these compounds showed low-nanomolar activities in p38α enzymatic and cell-based cytokine TNFα produc
- Mavunkel, Babu J.,Perumattam, John J.,Tan, Xuefei,Luedtke, Gregory R.,Lu, Qing,Lim, Don,Kizer, Darin,Dugar, Sundeep,Chakravarty, Sarvajit,Xu, Yong-jin,Jung, Joon,Liclican, Albert,Levy, Daniel E.,Tabora, Jocelyn
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scheme or table
p. 1059 - 1062
(2010/06/14)
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- HETEROCYCLIC DERIVATIVES AS ANTI-INFLAMMATORY AGENTS
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The present invention relates to some heterocyclic derivatives as anti-inflammatory agents. The compounds of this invention can be useful, for inhibition and/or prevention of inflammation and associated pathologies including inflammatory and autoimmune di
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Page/Page column 29
(2010/10/20)
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- The synthesis of substituted bipiperidine amide compounds as CCR3 antagonists
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Bipiperidine amide 1 has been identified as a CC chemokine receptor 3 (CCR3) antagonist. Optimization of its structure-activity relationship has resulted in the identification of cis (R,R)-4-[(3,4-dichlorophenyl)methyl]-3- hydroxymethyl-1′(6-quinolinylcar
- Ting, Pauline C.,Lee, Joe F.,Wu, Jie,Umland, Shelby P.,Aslanian, Robert,Cao, Jianhua,Dong, Youhao,Garlisi, Charles G.,Gilbert, Eric J.,Huang, Ying,Jakway, James,Kelly, Joseph,Liu, Zhidan,McCombie, Stuart,Shah, Himanshu,Tian, Fang,Wan, Yuntao,Shih, Neng-Yang
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p. 1375 - 1378
(2007/10/03)
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- Convenient methods for the synthesis of d4, d2 and d6 isotopomers of 4-(4-fluorobenzyl)piperidine
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Pure 4-(4-fluoro-[2,3,5,6-2H4]benzyl)piperidine was prepared via the Grignard reaction of 4-fluoro-[2,3,5,6-2H 4]bromobenzene and pyridine-4-aldehyde followed by consecutive deoxygenation and heteroatomic ring saturation in the presence of palladium on carbon catalyst. An improved method for the catalytic H/D exchange in benzylic positions of 4-(4-fluorobenzyl)piperidine and its d4 derivative has also been described. Copyright
- Proszenyak, Agnes,Agai, Bela,Tarkanyi, Gabor,Vida, Laszlo,Faigl, Ferenc
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p. 421 - 427
(2007/10/03)
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- NR2B-Selective N-Methyl-D-aspartate Antagonists: Synthesis and Evaluation of 5-Substituted Benzimidazoles
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Two classes of 5-substituted benzimidazoles were identified as potent antagonists of the NR2B subtype of the N-methyl-D-aspartate (NMDA) receptor. Selected compounds show very good selectivity versus the NR2A, NR2C, and NR2D subtypes of the NMDA receptor as well as versus hERG-channel activity and α1-adrenergic binding. Benzimidazole 37a shows excellent activity in the carrageenan-induced mechanical hyperalgesia assay in rats as well as good pharmacokinetic behavior in dogs.
- McCauley, John A.,Theberge, Cory R.,Romano, Joseph J.,Billings, Susan B.,Anderson, Kenneth D.,Claremon, David A.,Freidinger, Roger M.,Bednar, Rodney A.,Mosser, Scott D.,Gaul, Stanley L.,Connolly, Thomas M.,Condra, Cindra L.,Xia, Menghang,Cunningham, Michael E.,Bednar, Bohumil,Stump, Gary L.,Lynch, Joseph J.,Macaulay, Alison,Wafford, Keith A.,Koblan, Kenneth S.,Liverton, Nigel J.
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p. 2089 - 2096
(2007/10/03)
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- 2-[(4-BENZYL)-1-PIPERIDINYL)METHYL]BENZIMIDAZOLE-5-OL DERIVATIVES AS NR2B RECEPTOR ANTAGONISTS
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2-[(4-Benzyl)-1-piperidinyl)-methyl]benzimidazole-5-ol derivatives are NMDA NR2B receptor antagonists useful in the treatment of pain and other NMDA mediated diseases.
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- Cyclic amine compounds as CCR5 antagonists
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A compound of formula (I) (wherein R1is a hydrogen atom, a hydrocarbon group which may be substituted, a non-aromatic heterocyclic group which may be substituted, R2is a hydrocarbon group which may be substituted, a non-aromatic heterocyclic group which may be substituted, or R1and R2may combine to each other together with A to form a heterocyclic group which may be substituted; A is N or N+—R5.Y?(R5is a hydrocarbon group; Y?is a counter anion); R3is a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; n is 0 or 1; R4is a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, an alkoxy group which may be substituted, an aryloxy group which may be substituted, or an amino group which may be substituted, E is a divalent aliphatic hydrocarbon group which may be substituted by group(s) other than oxo; G1is a bond, CO or SO2; G2is CO, SO2, NHCO, CONH or OCO; J is methine or a nitrogen atom; and each of Q and R is a bond or a divalent C1-3aliphatic hydrocarbon which may be substituted; provided that J is methine when G2is OCO, that one of Q and R is not a bond when the other is a bond and that each of Q and R is not substituted by oxo group(s) when G1is a bond) or a salt thereof has a potent CCR5 antagonistic activity and can be advantageously used for the treatment or prevention of infectious disease of various HIV in human (e.g. AIDS).
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- UREA COMPOUNDS, PROCESS FOR PRODUCING THE SAME AND USE THEREOF
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A compound of the formula: [whereinR1 is a hydrocarbon group which may be substituted;R2 is a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted;R3 is halogen atoms, a carbam
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- Synthesis and resolution of racemic eliprodil and evaluation of the enantiomers of eliprodil as NMDA receptor antagonists
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A short synthesis of the NMDA receptor antagonist (rac)-Eliprodil (9) and its resolution into the enantiomers by chiral HPLC is described. The enantiomers (R)-9 and (S)-9 were found to exhibit markedly different affinities for NR2B subunit containing NMDA
- Pabel, Joerg,Hoefner, Georg,Wanner, Klaus Th.
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p. 1377 - 1380
(2007/10/03)
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- Ketanserin Analogues: Structure-Affinity Relationships for 5-HT2 and 5-HT1C Serotonin Receptor Binding
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Ketanserin is the prototypic 5-HT2 serotonin antagonist; although it has been an important tool for the study of serotonin pharmacology, it has had relatively little impact on drug design because remarkably little is known about its structure-affinity relationships.Furthermore, ketanserin also binds at 5-HT1C receptors and even less is known about the influence of its structural features on 5-HT1C receptor affinity.The present study reveals that the fluoro and carbonyl groups of the 4-fluorobenzoyl portion of ketanserin make small contributions to 5-HT2 binding and that the intact benzoylpiperidine moiety is an important feature.Ring opening of the piperidine ring reduces affinity.Although the quinazoline-2,4-dione moiety also contributes to binding, it appears to play a smaller role and can be structurally simplified with retention of 5-HT2 affinity.N-(4-Phenylbutyl)-4-(4-fluorobenzoyl)piperidine (39), for example, binds with nearly tha same affinity (Ki=5.3 nM) as ketanserin (Ki=3.5 nM).All of the compounds examined bind at 5-HT1C sites with lower affinity than ketanserin, and some of the simplified analogues bind with nearly 10 times the 5-HT2 versus 5-HT1C selectivity of ketanserin; however, none displays > 120 fold selectivity.Several of the compounds, such as the amide 32 and the urea 33 represent examples of new structural classes of 5-HT2 ligands.
- Herndon, Jeff L.,Ismaiel, Abd,Ingher, Stacy P.,Teitler, M.,Glennon, Richard A.
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p. 4903 - 4910
(2007/10/02)
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- Synthesis, Calcium-Channel-Blocking Activity, and Antihypertensive Activity of 4-(Diarylmethyl)-1-piperidines and Structurally Related
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A series of 4-(diarylmethyl)-1-piperidines and structurally related compounds were synthesized as calcium-channel blockers and antihypertensive agents.Compounds were evaluated for calcium-channel-blocking activity by determineng their ability to antagonize calcium-induced contractions of isolated rabbit aortic strips.The most potent compounds were those with fluoro substituents in the 3- and/or 4-positions of both rings of the diphenylmethyl group.Bis(4-fluorophenyl)acetonitrile analogue 79 was similar in potency to bis(4-fluorophenyl)methyl compound 1.The methylene analogue of 1 (78) and derivatives of 1 that contained a hydroxyl (76), carbamoyl (80), amino (81), or acetamido (82) substituent on the methyl group were less potent.In most cases substituents on the phenoxy ring, changes in the distance between the aryloxy group and the piperidine nitrogen, and the substitution of S, N(CH3), or CH2 for the oxygen atom of the aryloxy group had only a small to moderate effect on the potency.The best compounds in this series were more potent than verapamil, diltiazem, flunarizine, and lidoflazine, but were less potent than nifedipine.Compounds were evaluated for antihypertensive activity in spontaneusly hypertensive rats (SHR) at an oral dose of 30 mg/kg.Of the 55 compounds tested, only nine produced a statistically significant (p-1-piperidinyl>propoxy>-3-methoxyphenyl>ethanone (63), which produced a 35percent reduction in blood pressure and was similar in activity to nifedipine.At lower doses, however, 4--1-piperidine (93) was one of the most effective antihypertensive agents, producing reductions in blood pressure of 17 and 11percent at oral doses of 10 and 3 mg/kg, respectively; 63 was inactive at 10 mg/kg.
- Shanklin, James R.,Johnson, Christopher P.,Proakis, Anthony G.,Barrett, Richard J.
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p. 3011 - 3022
(2007/10/02)
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- Therapeutically useful 1-phenyl-2-piperidinoalkanol derivatives
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Compounds of the formula: STR1 wherein R1 is hydrogen, halogen, trifluoromethyl, alkyl, hydroxyl, alkyoxy, benzyloxy, alkanoyloxy, or benzoyloxy, or when R2 is hydroxyl or methoxy in the 4-position and R3 is hydrogen, R1 may also represent hydroxymethyl carbamoyl or alkoxycarbonyl, R2 is hydrogen, halogen, alkyl, hydroxyl, or alkoxy, R3 is hydrogen or alkyl, R4 is alkyl (in which case the compounds are (±)-erythro) or when R3 represents hydrogen, R4 may also be hydrogen, and R5 is hydrogen, halogen, alkyl, alkoxy, or three methoxy groups in the 3-, 4- and 5-positions and pharmaceutically acceptable acid addition salts thereof, with the exclusion of compounds wherein: (a) one of R1 and R2 is in the 4-position and is hydroxyl, alkoxy or benzyloxy, the other is in the 3-position and is hydrogen, hydroxyl, alkoxy or benzyloxy, and R3 and R5 are hydrogen and wherein: (b) R1 is in the 4-position and is halogen, R4 is methyl and R2, R3 and R5 are hydrogen, are useful as medicaments.
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