Sci. Animals are allowed to recover from the anaesthesia and the baseline thermal and mechanical nociceptive thresholds of all animals are assessed one week after the administration of CFA. (2003), (9):769-70).
Goldin et al., “Nomenclature of Voltage-Gated Sodium Channels”, Neuron vol. GR67330, a very high affinity ligand for 5-HT3 receptors," Nauyn-Schmiedeberg'"'"'s Arch Pharmacol., Vol. This article is licensed under a Creative Commons Attribution 3.0 Unported
The performance of 14 (alkoxy-phenyl)benzamide derivatives was studied on silica and alumina surfaces by normal phase TLC. 1-3, triangles represent total binding, open circles represent non-specific binding, and darkened circles represent specific binding. 1-11 (1993); Acquas, E., Carboni, E., Garau, L., and Di Chiara, G., "Blockage of acquisition of drug conditioned place aversion by 5-1-117-3, antagonists," Psychopharmacology, Vol. Evaluation of the compounds of the present invention was performed by incubating the radiolabeled agent with tissue homogenates known to contain these receptors. The external solution had the following composition: 140 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES; and adjusted to pH 7.4 with NaOH. The invention also provides a composition for the treatment of an abnormal conditions associated with an altered 5-HT-3 receptor binding, or with altered neurotransmitter receptor function regulated by 5-HT-3 receptors, in an individual comprising a therapeutically effective amount of the above compounds and a pharmaceutically acceptable carrier. The fluorine-18 isotope is a positron emitter with a half-life of 1.8 h. The bromine-76 isotope is a positron emitter with a half-life of 16 h. The bromine-75 isotope is a positron emitter with a half-life of 1.6 h. The iodine-124 isotope is a positron emitter with a half-life of 4.2 d. Upon annihilation of an antimatter positron with normal matter, 5 KeV gamma radiation occurs which are powerful enough to be detected outside the body. halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO2, —CO2R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)2R′, —NR′C(O)NR″R′″, —NHC(NH2)═NH, —NR′C(NH2)═NH, —NHC(NH2)═NR′, —S(O)R′, —S(O)2R′, —S(O)2NR′R″, —NR′S(O)2R″, —N3, perfluoro-C1-4 alkoxy, and perfluoro-C14 alkyl, —(CH2)1-4—OR′, —(CH2)1-4—NR′R″, —(CH2)1-4—SR′, —(CH2)1-4—SiR′R″R′″, —(CH2)1-4—OC(O)R′, —(CH2)1-4—C(O)R′, —(CH2)1-4—CO2R′, —(CH2)1-4CONR′R″, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R′, R″ and R′″ are independently selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C1-4 alkyl, and unsubstituted aryloxy-C1-4 alkyl.
No. Chung and Chung, “Sodium channels and neuropathic pain”, Novartis Foundation Symposium 261, 19-31 (2004).
Such techniques are known to those skilled in the art, and may be developed, using current technologies, into low or medium throughput assays for evaluating compounds for their ability to modulate sodium channel behavior. Other substituents for alkyl radicals, including heteroalkyl, alkylene, include for example, ═O, ═NR′, ═N—OR′, ═N—CN, ═NH, wherein R′ includes substituents as described above. Competitive binding experiments. To a mixture of 5-chloro-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2-fluorobenzoic acid (Preparation 4) (1.04 g, 2.69 mmol) in anhydrous tetrahydrofuran (70 mL) was added 1,1′-carbonyldiimidazole (1.09 g, 6.72 mmol). Further, the compounds of the present invention can be used for the diagnosis of an abnormal condition associated with altered 5-HT-3 receptor binding.
; Chung, J. M., et al., op. Chem., 272 (23): 14805-9). 0000055920 00000 n
3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547, 1983), non-degradable ethylene-vinyl acetate (Langer et al., J. Biomed. The test includes a heat source consisting of a projector lamp with a light beam focused and directed to a point on the tail of a mouse being tested. 1), pp. 2, pp.
Wolff Burger's Medicinal Chemistry and Drug Discovery Fifth Edition, vol. Fractions containing (S)-2,3-dimethoxy-5-tributyltin-N-(3-quinuclidinyl)benzamide were collected, the solvents evaporated, and the product redissolved in absolute ethanol (1 mg/mL). J. Clin. Conf., III, Proc., Vol. %PDF-1.7
In one aspect, the compounds are state or frequency dependent modifiers of the sodium channels, having a low affinity for the rested/closed state and a high affinity for the inactivated state. Coupling constants (J), when given, are reported in Hz (Hertz). The filtrate was concentrated in vacuo to afford a residue which was purified by silica gel column chromatography using 0-40% ethyl acetate in hexanes as an eluent to afford the title compound as a white solid (0.068 g, 25% yield): 1H NMR (300 MHz, DMSO-d6) δ 12.08 (br s, 1H), 7.81 (d, J=5.5 Hz, 1H), 7.66-7.54 (m, 2H), 7.44 (s, 1H), 7.11 (d, J=8.4 Hz, 1H), 5.24 (s, 2H), 2.89 (s, 6H); MS (ES−) m/z 453.0, 455.0 (M−1). The standard density of 51 compounds, were drawn into the Hyperchem program and optimized using semi-empirical AM1 method and predicted using multiple linear regression (MLR). The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). Following the procedure as described in PREPARATION 66, Step 2 and making non-critical variations to replace 3-bromo-4-(3-chloro-4-(trifluoromethoxy)phenoxy)benzoate with methyl 4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-2-fluoro-5-iodobenzoate and to replace (2-methoxypyridin-3-yl)boronic acid with 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane, the title compound as a colorless solid (0.17 g, 16% yield): 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J=8.1 Hz, 1H), 7.85 (d, J=2.7 Hz, 1H), 7.40 (d, J=2.7 Hz, 1H), 6.96 (dd, J=11.2, 17.7 Hz, 1H), 6.42 (d, J=11.7 Hz, 1H), 5.83 (d, J=17.6 Hz, 1H), 5.38 (d, J=11.2 Hz, 1H), 5.35-5.26 (m, 1H), 3.91 (s, 3H), 1.39 (d, J=6.2 Hz, 6H); MS (ES+) m/z 366.0, 368.0 (M+1). Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal. Pharmacol., Vol. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
The reaction mixture was stirred at ambient temperature for 3 h and then the solvent was concentrated in vacuo to afford the title compound as a white powder (1.64 g, 95%): 1H NMR (300 MHz, CDCl3) δ 9.72 (br, 1H), 8.15 (d, J=7.3 Hz, 1H), 7.39-7.36 (m, 1H), 7.20 (d, J=2.8 Hz, 1H), 7.00 (dd, J=2.8, 9.0 Hz, 1H), 6.68 (d, J=10.9 Hz, 1H); MS (ES−) m/z 383.0, 385.0 (M−1).
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