- An improved large-scale preparation of benzimidazole-2-sulfonic acids and 2-chlorobenzimidazoles
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An improved method for the preparation of benzimidazole-2-sulfonic acids from 2-mercaptobenzimidazoles has been developed which utilizes aqueous sodium percarbonate. 2-chlorobenzimidazoles were obtained in high yield from the corresponding sulfonic acids upon reaction with PCl5 in POCl3 on a gram-mole scale.
- Hinkley, Jack M.,Porcari, Anthony R.,Walker II, John A.,Swayze, Eric E.,Townsend, Leroy B.
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Read Online
- Disrupting the Conserved Salt Bridge in the Trimerization of Influenza A Nucleoprotein
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Antiviral drug resistance in influenza infections has been a major threat to public health. To develop a broad-spectrum inhibitor of influenza to combat the problem of drug resistance, we previously identified the highly conserved E339?R416 salt bridge of the nucleoprotein trimer as a target and compound 1 as an inhibitor disrupting the salt bridge with an EC50 = 2.7 μM against influenza A (A/WSN/1933). We have further modified this compound via a structure-based approach and performed antiviral activity screening to identify compounds 29 and 30 with EC50 values of 110 and 120 nM, respectively, and without measurable host cell cytotoxicity. Compared to the clinically used neuraminidase inhibitors, these two compounds showed better activity profiles against drug-resistant influenza A strains, as well as influenza B, and improved survival of influenza-infected mice.
- Woodring, Jennifer L.,Lu, Shao-Hung,Krasnova, Larissa,Wang, Shih-Chi,Chen, Jhih-Bin,Chou, Chiu-Chun,Huang, Yi-Chou,Cheng, Ting-Jen Rachel,Wu, Ying-Ta,Chen, Yu-Hou,Fang, Jim-Min,Tsai, Ming-Daw,Wong, Chi-Huey
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supporting information
p. 205 - 215
(2020/01/02)
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- Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening
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Here we report the discovery of a selective inhibitor of Aurora A, a key regulator of cell division and potential anticancer target. We used the atom category extended ligand overlap score (xLOS), a 3D ligand-based virtual screening method recently developed in our group, to select 437 shape and pharmacophore analogs of reference kinase inhibitors. Biochemical screening uncovered two inhibitor series with scaffolds unprecedented among kinase inhibitors. One of them was successfully optimized by structure-based design to a potent Aurora A inhibitor (IC50 = 2 nM) with very high kinome selectivity for Aurora kinases. This inhibitor locks Aurora A in an inactive conformation and disrupts binding to its activator protein TPX2, which impairs Aurora A localization at the mitotic spindle and induces cell division defects. This phenotype can be rescued by inhibitor-resistant Aurora A mutants. The inhibitor furthermore does not induce Aurora B specific effects in cells.
- Kilchmann, Falco,Marcaida, Maria J.,Kotak, Sachin,Schick, Thomas,Boss, Silvan D.,Awale, Mahendra,G?nczy, Pierre,Reymond, Jean-Louis
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p. 7188 - 7211
(2016/09/09)
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- MEGLUMINE SALT FORMULATIONS OF 1-(5,6-DICHLORO-1H-BENZO[D]IMIDAZOL-2-YL)-1H-PYRAZOLE-4-CARBOXYLIC ACID
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The meglumine salt of 1-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)-1H-pyrazole-4-carboxylic acid (compound (1)) and pharmaceutically acceptable formulations thereof are described. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by prolyl hydroxylase activity.
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Page/Page column 29
(2013/05/21)
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- PIPERIDINYL BENZOIMIDAZOLE DERIVATIVES AS MPGES-1 INIHIBITORS
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A compound of formula (I) as well as pharmaceutically acceptable salts thereof, and a pharmaceutical composition comprising the compound. The compound is useful for the treatment of disorder selected from inflammatory diseases, pain, auto-immune disease, breathing disorders, fever, cancer, inflammation related anorexia, overactive bladder, familial adenomatous polyposis (FAP) condition, neurodegenerative diseases, bone diseases and cardiovascular diseases.
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Page/Page column 29
(2012/09/21)
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- MICROSOMAL PROSTAGLANDIN E SYNTHASE-1 (MPGES1) INHIBITORS
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A compound of formula (I): as well as pharmaceutically acceptable salts thereof, and a pharmaceutical composition comprising the compound. The compound is useful for the treatment of disorder selected from inflammatory diseases, nociceptive pain, auto-imm
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Page/Page column 69
(2011/04/14)
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- BENZOIMIDAZOLES AS PROLYL HYDROXYLASE INHIBITORS
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The present invention is directed to benzoimidazole compounds of the formula (1) and enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof. Compounds of the present invention are useful in pharmaceutical compositions and met
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Page/Page column 60
(2009/12/05)
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- Synthesis and in vitro antimicrobial activity of some novel substituted benzimidazole derivatives having potent activity against MRSA
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The novel benzimidazole derivatives (3, 5, 8, 9, 12-14, 18-41) were prepared in this paper and the antimicrobial activities of these compounds against Staphylococcus aureus, methicillin-resistant S. aureus (MRSA, standard and clinical isolates), Bacillus subtilis, Escherichia coli and Candida albicans were evaluated. Compounds 24-26 which have no substitution of N-1 position displayed better antibacterial activities than those of standards (ciprofloxacin, ampicillin and sultamicillin) against both the drug-resistant bacteria (MRSA, standard and clinical isolates). These derivatives (24-26), 2,5,6-trihalogenobenzimidazole analogues (8, 12), 5,6-dichloro-2-amino derivative (13), and 5-chloro-2-(4-benzyloxyphenyl)benzimidazole (35) exhibited the most potent antibacterial activity with MIC 3.12 μg/ml against S. aureus.
- Tuncbilek, Meral,Kiper, Tulug,Altanlar, Nurten
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scheme or table
p. 1024 - 1033
(2009/09/06)
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- Design, syntheses, and structure-activity relationships of novel NPY Y5 receptor antagonists: 2-{3-Oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl}benzimidazole derivatives
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Design, syntheses, and structure-activity relationships of a novel class of 2-{3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl}benzimidazole NPY Y5 receptor antagonists are described. The benzimidazole structures were newly designed based on the urea linkage of our prototype Y5 receptor antagonists (2 and 3). By optimizing substituents on the benzimidazole core part of the lead compound 5a, we were able to develop a potent, orally available, and brain-penetrable Y5 selective antagonist (5k). Crown Copyright
- Ogino, Yoshio,Ohtake, Norikazu,Nagae, Yoshikazu,Matsuda, Kenji,Moriya, Minoru,Suga, Takuya,Ishikawa, Makoto,Kanesaka, Maki,Mitobe, Yuko,Ito, Junko,Kanno, Tetsuya,Ishihara, Akane,Iwaasa, Hisashi,Ohe, Tomoyuki,Kanatani, Akio,Fukami, Takehiro
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scheme or table
p. 5010 - 5014
(2009/05/07)
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- BENZIMIDAZOLES WITH A HETERO SPIRO-DECANE RESIDUE AS NPY-Y5 ANTAGONISTS
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The present invention relates to compounds of formula (I), or a pharmaceutically acceptable salts, solvates, stereoisomers thereof, formula (I), R1 may be C1-C4 alkyl, aryl or heteroaryl, which may be substituted by one or more: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano; R2 may be halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano, nitro; or aryl, heteroaryl or heterocycle, which may be substituted by one or more: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano; or R2 may correspond to -0-R3; R3 is a 6-membered aromatic carbocyclic ring which may contain 1 or 2 nitrogen X is carbon or oxygen; Z is carbon or nitrogen; G is a fused 6-membered aromatic carbocyclic ring which may contain 1 or 2 nitrogen; m may be 0 or an integer ranging from 1 to 4; processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, as NPY- Y5 receptor antagonists.
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Page/Page column 35-36
(2008/12/08)
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- BENZIMIDAZOLE DERIVATIVES AND MEDICAL USES THEREOF
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The present invention providesbenzimidazole derivatives represented by the following formula (I) or pharmaceutically acceptable salts thereof, or prodrugs thereof, which exert an inhibitory activity on sodium-dependent nucleoside transporter 2 and are useful for a disease associated with an abnormality of plasma uric acid level. The compounds of the present invention are useful for the prevention or treatment of gout, hyperuricemia, urinary lithiasis, hyperuricemic nephropathy or the like. In the formula, n is 1 or 2; R1 and R2 are H, a halogen atom, cyano group, optionally substituted alkyl group, optionally substituted aryl group or the like; R3 is H, a halogen atom, optionally substituted alkyl group or the like; R9 and R5 are H, a halogen atom, OH or the like; and R6 and RX are H or OH: RY is F or OH.
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Page/Page column 28
(2008/06/13)
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- 2-Substituted benzimidazole piperidines analogs as selective melanin concentrating hormone receptor antagonists for the treatment of obesity and related disorders
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The present invention discloses compounds of formula I wherein Ar, Y, m, n, R1 and R4 are herein defined, said compounds being novel antagonists for melanin-concentrating hormone (MCH), as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such MCH antagonists as well as methods of using them to treat obesity, metabolic disorders, eating disorders such as hyperphagia, and diabetes.
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Page/Page column 31
(2008/06/13)
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- BENZIMIDAZOLE DERIVATIVES AND THEIR USE AS VANILLOID RECEPTOR LIGANDS
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Compounds of formula (I) are useful in the treatment of vanilloid-receptor-meditated diseases, such as inflammatory or neuropathic pain and diseases involving sensory nerve function such as asthma, rheumatoid arthritis, osteoarthritis, inflammatory bowel disorders, urinary incontinence, migraine and psoriasis.
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- New 2-piperazinylbenzimidazole derivatives as 5-HT3 antagonists. Synthesis and pharmacological evaluation
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A series of 2-piperazinylbenzimidazole derivatives were prepared and evaluated as 5-HT3 receptor antagonists. Their 5-HT3 receptor affinities were evaluated by radioligand binding assays, and their abilities to inhibit the 5-HT-induced Bezold-Jarisch reflex in anesthetized rats were determined. Compound 7e (lerisetron, pK(i) = 9.2) exhibited higher affinity for the 5- HT3 receptor than did tropisetron and granisetron, while compound 7q (pK(i) = 7.5) had very low affinity for this receptor, showing that substitution on the N1 atom of the benzimidazole ring is essential for affinity and activity. The effect of substitution on the aromatic ring of benzimidazole by several substituents in different positions is also discussed. A strong correlation between the 5-HT3 antagonistic activity of the studied compounds and the position of substitution on the aromatic ring was established. Thus, while the 4-methoxy derivative 7m showed weak affinity for the 5-HT3 receptor (pK(i) = 6.7), the 7-methoxy derivative 7n exhibited the highest affinity (pK(i) = 9.4). Compounds 7e and 7n are now under further investigation as drugs for the treatment of nausea and emesis evoked by cancer chemotherapy and radiation.
- Orjales, Aurelio,Mosquera, Ramón,Labeaga, Luis,Rodes, Rosa
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p. 586 - 593
(2007/10/03)
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- Polysubstituted benzimidazoles as antiviral agents
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Polysubstituted benzimidazoles and pharmaceutical compositions containing them as the active ingredients. These compounds and compositions exhibit antiviral activity against viruse of the herpes family, particularly human cytomegalovirus and herpes simplex viruses (HSV).
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- Design, Synthesis, and Antiviral Activity of Certain 2,5,6-Trihalo-1-(β-D-ribofuranosyl)benzimidazoles
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A new series of 2-substituted 5,6-dichlorobenzimidazole ribonucleosides has been synthesized and tested for activity against two human herpes viruses and for cytotoxicity. 2,5,6-Trichloro-1-(β-D-ribofuranosyl)benzimidazole (TCRB) was prepared by ribosylation of the heterocycle 2,5,6-trichlorobenzimidazole followed by a removal of the protecting groups.The 2-bromo derivative (BDCRB) was made in a similar fashion from 2-bromo-5,6-dichlorobenzimidazole.In contrast, the 2-iodo derivative presented a more difficult problem since the appropriate heterocycle was unavailable.This prompted us to prepare the 2-amino derivative followed by nonaqueous diazotization and removal of the blocking groups.Biological evaluation revealed marked differences in the activities of these compounds and the closely related known compound 5,6-dichloro-1-(β-D-ribofuranosyl)benzimidazole (DRB).DRB was weakly active against both human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1), (IC50's = 42 and 30 μM, respectively) but was cytotoxic to uninfected human foreskin fibroblasts and KB cells in the same dose range.Similar results were obtained with the heterocycle 2,5,6-trichlorobenzimidazole.In marked contrast, the ribonucleoside of 2,5,6-trichlorobenzimidazole (TCRB) was active against HCMV (IC50 = 2.9 μM, plaque assay; IC90 = 1.4 μM, yield assay) but only weakly active against HSV-1 (IC50 = 102 μM, plaque assay).Little to no cytotoxicity was observed in HFF and KB cells at concentrations up to 100 μM.By changing the substituent at the 2-position from chlorine to bromine (BDCRB), a 4-fold increase in activity against HCMV was observed without any significant increase in cytotoxicity.In contrast, the 2-I and 2-NH2 derivatives were only weakly active against HCMV and HSV-1 with activity not well-separated from cytotoxicity.These data establish that for maximum activity against HCMV with separation from cytotoxicity, ribose is preferred at the 1-position and that Cl or Br is apparently preferred at the 2-position.The activity and selectivity of both TCRB and BDCRB were better than that observed with either ganciclovir or foscarnet.
- Townsend, Leroy B.,Devivar, Rodrigo V.,Turk, Steven R.,Nassiri, M. Reza,Drach, John C.
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p. 4098 - 4105
(2007/10/02)
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- Polysubstituted benzimidazoles as antiviral agents
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This invention relates to novel polysubstituted benzimidazoles and compositions and their use in the treatment of viral infections. The polysubstituted benzimidazoles and compositions of the present invention exhibit antiviral properties against viruses of the herpes family, particularly human cytomegalovirus (HCMV) and herpes simplex viruses (HSV). Preferred polysubstituted benzimidazoles of the invention are 2,5,6-Trichloro-1-(β-D-5-deoxyribofuranosyl)benzimidazole and 2-bromo-5,6-dichloro-1-(5-deoxy-β-D-ribofuranosyl)benzimidazole.
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- Polysubstituted benzimidazole nucleosides as antiviral agents
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This invention relates to novel polysubstituted benzimidazole nucleosides and compositions and their use in the treatment of viral infections, particulary those caused by human cytomegalovirus and herpes simplex virus. Such substituted compounds exhibit a
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