Potential anxiolytic agents. 3. Novel A-ring modified pyrido[1,2-a]benzimidazoles (original) (raw)
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Journal of Medicinal Chemistry, 2006
Squirrel monkey RPI lever pressing assay Elemental analyses and HPLC data S2 General Methods. Melting points were obtained on a Leica Galen III hot stage and are uncorrected. Proton NMR spectra were obtained using either a Bruker AM360 or a Bruker DPX-400 spectrometer. Mass spectra were recorded on a Waters Micromass ZMD or ZQ operating in an electrospray (ES) mode. (Note that only the strongest peaks from the mass spectra are reported below.) Elemental analysis for carbon, hydrogen, and nitrogen were performed by Butterworth Laboratories Ltd. Unless otherwise stated, high performance liquid chromatography (HPLC) analysis was performed on a Hewlett Packard HP1100 instrument using a Supelcosil™ ABZ+Plus 15 cm × 4.6 mm, 5µm column, eluting with acetonitrile/water (containing 0.1% trifluoroacetic acid). Analytical thin-layer chromatography (TLC) was conducted on precoated silica gel 60 F 254 plates (Merck). Visualisation of the plates was accomplished by using UV light and/or iodine and/or aqueous potassium permanganate solution. Chromatography was conducted on silica gel 60, 220-440 mesh (Fluka) under low pressure. Solutions were evaporated on a Büchi rotary evaporator under reduced pressure. All starting materials were obtained from commercial sources and used as received unless otherwise indicated. 3-Bromo-7-methyl-imidazo[1,2-b]pyridazine (13). To a stirred solution of 7-methyl-imidazo[1,2-b]pyridazine (30.1 mg, 0.226 mmol) (prepared as described by Pollak et al. Tetrahedron 1968, 24, 2623) and sodium acetate (27.4 mg, 0.334 mmol) in glacial acetic acid (1 mL) was added dropwise, over 2 min, bromine (12.2 µL, 0.237 mmol). The mixture was stirred at room temperature for 20 min, then partitioned carefully between saturated aqueous NaHCO 3 (15 mL) and ethyl acetate (20 mL). The aqueous layer, which had a pH of 9, was extracted further with ethyl acetate (2 x 20 mL). The combined organic extracts were dried (Na 2 SO 4) and evaporated. The residue was purified by flash chromatography (silica gel, ethyl acetate) to leave 47.3 mg (99%) of 13: 1 H NMR (400 MHz, CDCl 3) δ 2.45 (3H, s), 7.70 (2H, s), 8.30 (1H, s). 3'-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-2-carbonitrile (18a). A mixture of 2-bromobenzonitrile (9.1 g, 50 mmol), 3-aminobenzeneboronic acid monohydrate (11.6 g, 75 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.73 g, 1.5 mmol) in dimethoxyethane (50 mL) and 2 M aqueous sodium carbonate (25 mL) was heated at 80 °C for 20 h. After cooling to ambient temperature the reaction was partitioned between ethyl acetate (400 mL) and water (400 mL). The organic layer was washed with brine (400 mL), dried (Na 2 SO 4), and evaporated. Purification of the residue by flash chromatography (silica gel, 0-25% EtOAc/isohexane) gave 9.5 g (98%) of 3'-aminobiphenyl-2-carbonitrile as a colourless oil that solidified on standing to afford a white solid:
Journal of Medicinal Chemistry, 2008
A series of imidazopyridine acetamides were synthesized to evaluate the effects of structural changes at both central (CBRs) and peripheral benzodiazepine receptors (PBRs). These changes include the introduction of polar substituents or ionizable functional groups at the 2-and 8-position of the imidazopyridine skeleton. The results suggest that substituents endowed with hydrogen bonding acceptor and/or donor properties in the para position of the phenyl ring lead to high affinity for PBR. In electrophysiological studies, it was found that compounds 9, 12, 13, and 28 markedly enhanced GABA-evoked Clcurrents in Xenopus oocytes expressing R 1 2 γ 2 GABA A receptors. The capability of flumazenil to reduce the stimulatory effect exerted by compound 9 supports the conclusion that the modulatory effects of the examined compounds occur involving the CBR. The ability of compound 16 to increase GABA A receptor-mediated miniature inhibitory postsynaptic currents in CA1 pyramidal neurons is indicative of its ability to stimulate the local synthesis and secretion of neurosteroids. Figure 3. Compound 16 increases GABAA receptor-mediated mIPSCs in rat CA1 pyramidal neurons in a neurosteroid-dependent manner. (A) Sample traces of mIPSCs recorded before (control), after 30 min of continuous bath application of rat hippocampal slices with compound 16 (30 µM), or in the presence of the GABA A receptor antagonist bicuculline (20 µM). (B) Averaged traces of multiple mIPSCs recorded during a 3 min period before (control), after 30 min of application of compound 16, and after 30 min of co-application of compound 16 and finasteride (1 µM). (C) Values represent the mean percent change ( SEM (n ) 6) in mIPSC amplitude induced by compound 16 with or without the application of finasteride. (D) Averaged traces of multiple mIPSCs showing the increase in decay time induced by compound 16 and the reversal of this effect by finasteride. (E) Values represent the mean percent change ( SEM (n ) 6) in mIPSC decay time constant induced by compound 16 with or without the application of finasteride. *p < 0.05 vs control.
Journal of Medicinal Chemistry, 2008
This research paper aims the preparation of substituted tetrahydroquino [7,8-b] [1,4]benzodiazepine-3-carboxylic acids 4a, 4b and 4c. Reaction of 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-1,4-dihydroquinoline-3-carboxylic acid (6) with each of 2-amino-5methylbenzoic acid (5a), 2-amino-5-flourobenzoic acid (5b), and 2-amino-5-nitrobenzoic acid (5c) yielded 8-nitro-7-substituted anilino-1,4-dihydroquinoline-3-carboxylic acids 7 (a-c) with low yields. Reduction of 7 with sodium dithionite or stannous chloride resulted in the production of 8-amino-7-substituted aniline-1,4-dihydro-quinoline-3-carboxylic acids 10 (a-c). Polyphosphoric acid (PPA) catalyzed thermal lactamization of 10 resulted in the production of 4 (a-c). All intermediates and target compounds were characterized using elemental analysis, NMR, IR and MS spectral data. The prepared targets and the intermediates have shown interesting antibacterial activity mainly against Gram positive strains. In particular, the reduced intermediates 10 (a-c) showed good activity against standard S. aureus (MIC = 0.05 -0.19 µg/mL). Intermediates 10 (a-c) have also shown reasonable activity against resistant gram positive strains. The targets 4b and 4c have comparable activity to the reference against standard gram positive strains.
J Med Chem, 2006
Squirrel monkey RPI lever pressing assay Elemental analyses and HPLC data S2 General Methods. Melting points were obtained on a Leica Galen III hot stage and are uncorrected. Proton NMR spectra were obtained using either a Bruker AM360 or a Bruker DPX-400 spectrometer. Mass spectra were recorded on a Waters Micromass ZMD or ZQ operating in an electrospray (ES) mode. (Note that only the strongest peaks from the mass spectra are reported below.) Elemental analysis for carbon, hydrogen, and nitrogen were performed by Butterworth Laboratories Ltd. Unless otherwise stated, high performance liquid chromatography (HPLC) analysis was performed on a Hewlett Packard HP1100 instrument using a Supelcosil™ ABZ+Plus 15 cm × 4.6 mm, 5µm column, eluting with acetonitrile/water (containing 0.1% trifluoroacetic acid). Analytical thin-layer chromatography (TLC) was conducted on precoated silica gel 60 F 254 plates (Merck). Visualisation of the plates was accomplished by using UV light and/or iodine and/or aqueous potassium permanganate solution. Chromatography was conducted on silica gel 60, 220-440 mesh (Fluka) under low pressure. Solutions were evaporated on a Büchi rotary evaporator under reduced pressure. All starting materials were obtained from commercial sources and used as received unless otherwise indicated. 3-Bromo-7-methyl-imidazo[1,2-b]pyridazine (13). To a stirred solution of 7-methyl-imidazo[1,2-b]pyridazine (30.1 mg, 0.226 mmol) (prepared as described by Pollak et al. Tetrahedron 1968, 24, 2623) and sodium acetate (27.4 mg, 0.334 mmol) in glacial acetic acid (1 mL) was added dropwise, over 2 min, bromine (12.2 µL, 0.237 mmol). The mixture was stirred at room temperature for 20 min, then partitioned carefully between saturated aqueous NaHCO 3 (15 mL) and ethyl acetate (20 mL). The aqueous layer, which had a pH of 9, was extracted further with ethyl acetate (2 x 20 mL). The combined organic extracts were dried (Na 2 SO 4) and evaporated. The residue was purified by flash chromatography (silica gel, ethyl acetate) to leave 47.3 mg (99%) of 13: 1 H NMR (400 MHz, CDCl 3) δ 2.45 (3H, s), 7.70 (2H, s), 8.30 (1H, s). 3'-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-2-carbonitrile (18a). A mixture of 2-bromobenzonitrile (9.1 g, 50 mmol), 3-aminobenzeneboronic acid monohydrate (11.6 g, 75 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.73 g, 1.5 mmol) in dimethoxyethane (50 mL) and 2 M aqueous sodium carbonate (25 mL) was heated at 80 °C for 20 h. After cooling to ambient temperature the reaction was partitioned between ethyl acetate (400 mL) and water (400 mL). The organic layer was washed with brine (400 mL), dried (Na 2 SO 4), and evaporated. Purification of the residue by flash chromatography (silica gel, 0-25% EtOAc/isohexane) gave 9.5 g (98%) of 3'-aminobiphenyl-2-carbonitrile as a colourless oil that solidified on standing to afford a white solid:
Molecules, 2021
Background: Neurotic disturbances, anxiety, neurosis-like disorders, and stress situations are widespread. Benzodiazepine tranquillizers have been found to be among the most effective antianxiety drugs. The pharmacological action of benzodiazepines is due to their interaction with the supra-molecular membrane GABA-a-benzodiazepine receptor complex, linked to the Cl-ionophore. Benzodiazepines enhance GABA-ergic transmission and this has led to a study of the role of GABA in anxiety. The search for anxiolytics and anticonvulsive agents has involved glutamate-ergic, 5HT-ergic substances and neuropeptides. However, each of these well-known anxiolytics, anticonvulsants and cognition enhancers (nootropics) has repeatedly been reported to have many adverse side effects, therefore there is an urgent need to search for new drugs able to restore damaged cognitive functions without causing significant adverse reactions. Objective: Considering the relevance of epilepsy diffusion in the world, w...