- Antimalarial benzoheterocyclic 4-aminoquinolines: Structure-activity relationship, in vivo evaluation, mechanistic and bioactivation studies
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A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum. Structure-activity relationship studies led to the identification of highly promising analogues, the most potent of which had IC50s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4 × 10 mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively.
- Ongarora, Dennis S.B.,Strydom, Natasha,Wicht, Kathryn,Njoroge, Mathew,Wiesner, Lubbe,Egan, Timothy J.,Wittlin, Sergio,Jurva, Ulrik,Masimirembwa, Collen M.,Chibale, Kelly
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Read Online
- A new series of benzoxazole-based SIRT1 modulators for targeted therapy of non-small-cell lung cancer
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In an attempt to identify potential anticancer agents for non-small-cell lung cancer (NSCLC) targeting sirtuin 1 (SIRT1), the synthesis of a new series of benzoxazoles (3a – i) was carried out through a facile and versatile synthetic route. The compounds were evaluated for their cytotoxic effects on A549 human lung adenocarcinoma and NIH/3T3 mouse embryonic fibroblast cells using the MTT assay. 2-[(5-Nitro-1H-benzimidazol-2-yl)thio]-N-(2-methylbenzoxazol-5-yl)acetamide (3e) and 2-[(5-chloro-1H-benzimidazol-2-yl)thio]-N-(2-methylbenzoxazol-5-yl)acetamide (3g) were the most potent and selective anticancer agents in this series against the A549 cell line, with IC50 values of 46.66 ± 11.54 and 55.00 ± 5.00 μM, respectively. The flow cytometry-based apoptosis detection assay was performed to determine their effects on apoptosis in A549 cells. Both compounds induced apoptosis in a dose-dependent manner. The effects of compounds 3e and 3g on SIRT1 activity were determined. On the basis of in vitro studies, it was observed that compound 3g caused a significant decrease in SIRT1 levels in a dose-dependent manner, whereas compound 3e increased the SIRT1 levels. According to molecular docking studies, the substantial alteration in the type of action could be attributed to the difference between the interactions of compounds 3e and 3g with the same residues in the active site of SIRT1 (PDB code: 4IG9). On the basis of in silico ADME (absorption, distribution, metabolism, and excretion) studies, these compounds are predicted to possess favorable ADME profiles. According to the in vitro and in silico studies, compounds 3e and 3g, small-molecule SIRT1 modulators, were identified as potential orally bioavailable anticancer agents for the targeted therapy of NSCLC.
- Sever, Belgin,Akal?n ?ift?i, Gül?en,Alt?ntop, Mehlika Dilek
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- Green synthesis of therapeutically active 1,3,4-oxadiazoles as antioxidants, selective COX-2 inhibitors and their in silico studies
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A modest, competent and green synthetic procedure for novel coumarinyl-1,3,4-oxadiazolyl-2-mercaptobenzoxazoles 8i-t has been reported. Analysis of the docked (PDB ID: 5IKR; A-Chain) poses of the compounds illustrated that they adopt identical conformations to the extremely selective COX-2 inhibitor. The biological outcomes as well as computational study suggested that the compounds originated to have elevated resemblance towards COX-2 enzyme than COX-1. The compounds 8i, 8l, 8q, 8r, 8s and 8t emerged as most potent and selective COX-2 inhibitors in contrast with Mefenamic acid. The selectivity index of 8l, 8n and 8r was respectively found to be 33.95, 20.25 and 24.98 which manifested their high selectivity against COX-2. Interestingly, the compounds which were active as COX-2 inhibitors were also active as antioxidant agents.
- Nesaragi, Aravind R.,Kamble, Ravindra R.,Dixit, Shruti,Kodasi, Barnabas,Hoolageri, Swati R.,Bayannavar, Praveen K.,Dasappa, Jagadeesh Prasad,Vootla, Shyamkumar,Joshi, Shrinivas D.,Kumbar, Vijay M.
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supporting information
(2021/06/09)
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- Microwave facilitated one-pot three component synthesis of coumarin-benzoxazole clubbed 1,2,3-triazoles: Antimicrobial evaluation, molecular docking and in silico ADME studies
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4-((4-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)methyl)-2H-chromen-2-ones 7k–z were synthesized by conventional as well as microwave irradiation method in order to obtain antimicrobial agents. The present green synthetic protocol explores facile work up procedure with excellent yields (82–92%) and purity. Docking studies exhibited strong binding interactions with enzyme N-myristoyl transferase (PDB ID: 4CAW) with excellent C-score values. Compounds 7k–z were screened for their in vitro antimicrobial activities. The compounds 7w and 7 y exhibited excellent antimicrobial results for all the tested microorganisms at MICs ranging from 3.12 to 6.25 μg/ml in comparison with the marketed drugs.
- Nesaragi, Aravind R.,Kamble, Ravindra R.,Bayannavar, Praveen K.,Metre, Tukaram V.,Kariduraganavar, Mahadevappa Y.,Margankop, Sheetal B.,Joshi, Shrinivas D.,Kumbar, Vijay M.
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p. 3460 - 3472
(2021/10/02)
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- Three-Component Synthesis of 2-Alkylthiobenzoazoles in Aqueous Media
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A highly efficient three-component protocol for the synthesis of the 2-alkylthiobenzoazoles is described. Tetramethylthiuram disulfide (TMTD) cyclized with o -aminothiophenols, generating the intermediate 2-mercaptobenzothiazoles, and the successive C-S coupling with halogenated alkanes afforded a series of 2-alkyl-substituted thiobenzothiazoles smoothly in a one-pot process. This procedure could also be utilized for the preparation of 2-alkyl-substituted thiobenzoxazoles and 2-alkyl-substituted thiobenzimidazoles. Inexpensive and easily available starting materials, metal catalyst-free, broad substrate scope, and water as solvent are the features of this protocol.
- Chen, Jin-Quan,Dong, Zhi-Bing,Guo, Jia
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p. 1927 - 1933
(2020/07/03)
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- Metal-free C–H mercaptalization of benzothiazoles and benzoxazoles using 1,3-propanedithiol as thiol source
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A facile and effective C–H functionalization strategy for the synthesis of 2-mercaptobenzothiazoles and 2-mercaptobenzoxazoles is described. 1,3-Propanedithiol was employed to convert benzothiazoles and benzoxazoles to the corresponding heteroarylthiols in the presence of potassium hydroxide and DMSO. This novel protocol is featured by direct C–H mercaptalization of heteroarenes and a simple reaction system.
- Xiao, Yan,Jing, Bing,Liu, Xiaoxia,Xue, Hongyu,Liu, Yajun
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supporting information
p. 279 - 284
(2019/02/20)
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- Copper(I)-Catalyzed Tandem One-Pot Synthesis of 2-Arylthiobenzothiazoles and 2-Arylthiobenzoxazoles in Water
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An efficient tandem process for the preparation of 2-arylthiobenzothiazoles has been developed. By condensation of 2-aminobenzenethiol with tetramethylthiuram disulfide (TMTD), 2-mercaptobenzothiazoles was in situ generated, which susequently underwent coupling with iodobenzenes to give the desired 2-arylthiobenzothiazoles fluently in a one-pot manner. This method can also be used for the synthesis of 2-arylthiobenzoxazoles. Inexpensive metal catalyst and ligand, mild reaction temperature, and water as solvent make this protocol practically valuable and useful in organic synthesis.
- Liu, Xing,Zhang, Shi-Bo,Zhu, Hui,Dong, Zhi-Bing
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p. 11703 - 11711
(2018/10/02)
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- Preparation method of 2-mercaptobenzoxazole(thiazole) compounds taking 1,3-dimercaptopropane as mercapto source
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The invention belongs to the synthesis field of medicine chemical intermediate, and provides a preparation method of 2-mercaptobenzoxazole(thiazole) compounds taking 1,3-dimercaptopropane as a mercapto source. According to the preparation method, under inert gas protection, in dimethyl sulphoxide solvent, substituted benzoxazole(thiazole) and 1,3-dimercaptopropane are subjected to 120 to 140 DEG Cheating stirring in the presence of an alkali, after 12 to 24h of reaction, an obtained reaction solution is cooled to room temperature, and is subjected to acidifying post-treatment so as to obtaina product. The reaction conditions are simple; function group compatibility is excellent; yield is relatively high; the obtained 2-mercaptobenzoxazole(thiazole) compounds are important organic synthesis intermediates; application range in the field of chemical raw material, pesticide, and medicine is wide; and practical value and social and economic benefit are excellent.
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Paragraph 0030; 0031
(2018/10/02)
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- ANTIBIOTIC COMPOUNDS
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The present invention relates to antibiotic compounds of formula (I), to compositions containing these compounds and to methods of treating bacterial diseases and infections using the compounds. The compounds find application in the treatment of infection with, and diseases caused by, Gram-positive and/or Gram-negative bacteria, and in particular in the treatment of infection with, and diseases caused by, Neisseria gonorrhoeae.
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Page/Page column 67; 68; 81; 82; 182
(2018/03/25)
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- A [2 - [(5 - chloro - benzo oxazole - 2 - yl) (3 - oxo-butyl) amino] ethyl] carbamic acid tert-butyl preparation method (by machine translation)
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The invention discloses a [2 - [(5 - chloro - benzo oxazole - 2 - yl) (3 - oxo-butyl) amino] ethyl] carbamic acid tert-butyl preparation method, in order to ethylenediamine, vinyl, 2 - amino - 4 - chlorophenol and the like as raw materials, after five-step reaction to obtain the target product [2 - [(5 - chloro - benzo oxazole - 2 - yl) (3 - oxo-butyl) amino] ethyl] tert-butyl carbamate. The invention has simple operation, environment friendly, comprehensive yield is 52% more, than the existing 35.6% yield, with a remarkable enhancement, greatly reduces the production cost of the existing drugs, is suitable for industrial scale production. (by machine translation)
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Paragraph 0025; 0026; 0037; 0038; 0048; 0049; 0062-0064
(2017/04/19)
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- A su Wolei lives is an important intermediate for preparing method (by machine translation)
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The invention belongs to the field of medical technology, claims an important intermediate {2 - [(5 - chlorobenzene benzene and oxazole -2 yl) - (3 - keto - butyl) - amino] ethyl} - carbamic acid tert-butyl preparation method. The use of the toxicity is relatively small compound in place of the two connecting methyl ketene, the DBU, LDA, NaHMDS, KHMDS catalytic reaction such as, can in order to 90% high yield of the above formula (3) compound, and the HPLC of the crude product content of 99.5% or more, the method of the invention is suitable for industrial production. (by machine translation)
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Paragraph 0031; 0032
(2017/07/12)
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- OCTAHYDROPYRROLO [3, 4-c] PYRROLE DERIVATIVES AND USES THEREOF
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The invention relates to octahydropyrrolo [3, 4-c] pyrrole derivatives and uses thereof. Compounds and pharmaceutical compositions comprising the compounds provided herein are used for antagonizing orexin receptors. The invention also relates to processes for preparing the compounds and pharmaceutical compositions, and uses thereof in treating or preventing a disease related to orexin receptors.
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Paragraph 00186
(2017/07/04)
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- An environmentally benign and efficient synthesis of substituted benzothiazole-2-thiols, benzoxazole-2-thiols, and benzimidazoline-2-thiones in water
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An efficient and practical method for the one-step synthesis of benzothiazole-2-thiols, benzoxazole-2-thiols and benzimidazoline-2-thiones by cyclization of 2-aminothiophenols, 2-aminophenols, and 1,2-phenylenediamines with tetramethylthiuram disulfide (TMTD) in water was described. The features of this method include metal/ligand-free, excellent yield, short reaction time and broad substrate scope. The method provides a facile and convenient preparation of some potentially biologically active compounds.
- Liu, Xing,Liu, Min,Xu, Wan,Zeng, Meng-Tian,Zhu, Hui,Chang, Cai-Zhu,Dong, Zhi-Bing
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p. 5591 - 5598
(2017/12/06)
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- Selective synthesis of 2-aminobenzoxazoles and 2-mercaptobenzoxazoles by using o-aminophenols as starting material
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2-Aminobenzoxazoles and 2-mercaptobenzoxazoles were selectively synthesized by treating o-aminophenols with dithiocarbamates and tetramethylthiuram disulfide (TMTD), respectively. With the promotion of NaH/CuI, the reaction of o-aminophenols with dithioca
- Liu, Min,Zeng, Meng-Tian,Xu, Wan,Wu, Li,Dong, Zhi-Bing
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supporting information
p. 4352 - 4356
(2017/10/17)
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- Elemental sulfur as a sulfuration agent in the copper-catalyzed C-H bond thiolation of electron-deficient arenes
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By utilizing elemental sulfur as the thiolation agent and oxidant, a copper-catalyzed direct C-H bond thiolation of electron-deficient arenes was demonstrated. Various electron-deficient arenes were proved to be suitable for this transformation. Preliminary mechanistic studies indicated that this reaction underwent a radical pathway, in which the trisulfur radical anion (S3-) might play a vital role. Meanwhile, KIE experiments suggested that C-H bond cleavage was not involved in the rate-determining step.
- Yan, Haiming,Huang, Zhiliang,Chen, Meng,Li, Cuiting,Chen, Ya,Gao, Meng,Lei, Aiwen
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supporting information
p. 8276 - 8279
(2017/10/23)
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- PROCESS FOR THE PREPARATION OF SUVOREXANT AND INTERMEDIATES USEFUL IN THE SYNTHESIS OF SUVOREXANT
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A novel processes for the preparation of suvorexant (formula I), its related compounds and its intermediates that are simple, economical and commercially viable. (I)
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Paragraph 0142-0143
(2016/07/05)
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- EHPATITIS B ANTIVIRAL AGENTS
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The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, esters, or prodrugs thereof: X-A-Y-Z-L-R1 (I) which inhibit the protein(s) encoded by hepatitis B virus (HBV) or interfere with the function of the HBV life cycle of the hepatitis B virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HBV infection. The invention also relates to methods of treating an HBV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.
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Page/Page column 47
(2016/11/28)
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- Process for the preparation of an intermediate for an orexin receptor antagonist
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The present invention is directed to processes for preparing an intermediate for a diazepane compound which is an antagonist of orexin receptors, and which is useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved.
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Page/Page column 9
(2017/02/02)
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- Lanthanide-catalyzed cyclocarbonylation and cyclothiocarbonylation: A facile synthesis of benzannulated 1,3-diheteroatom five- and six-membered heterocycles
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La[N(SiMe3)2]3 proves to be an efficient catalyst system for the cyclocarbonylation of 1,2-disubstituted benzenes with isocyanates. In this approach, aryl/alkyl isocyanates react with o-phenylenediamine, o-aminophenol, o-aminothiophenol, catechols and anilines ortho-substituted by CH2NH2 and CONH2 to form, respectively, the corresponding benzimidazolones, benzoxazolones, benzothiazolones, benzodioxolones, 3,4-dihydroquinazolin-2(1H)-one, and quinazolinediones. These results represent the first example of lanthanide-catalyzed carbonylation. This methodology is also applicable for the preparation of various benzannulated 1,3-diheteroatom cyclic thioketones starting from aryl/alkyl isothiocyanates or CS2 in good to excellent yields. Based on the results of experiments performed using an o-aminobenzamido dianion lanthanide complex, a general mechanism, involving the tandem reaction of two lanthanide-ligand bonds with one heterocumulene molecule, is proposed as well.
- Jing, Yufeng,Liu, Ruiting,Lin, Yanghui,Zhou, Xigeng
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p. 1117 - 1125
(2014/08/18)
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- Regioselective thiolation of arenes and heteroarenes: C-H functionalization strategy for C-S bond formation
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A facile transition-metal-free oxidative cross-dehydrogenative coupling reaction involving selective formation of a C-S bond leading to the synthesis of arylthiobenzoxazoles, heteroarylthiobenzoxazoles, and arylthiobenzothiazoles has been described. This highly regioselective C-H functionalization reaction with electron-rich aromatic systems including heteroaromatics is achieved by reversing the reactivity of sulfur in the presence of a suitable oxidant and strong acid. (Chemical Equation Presented).
- Varun, Begur Vasanthkumar,Prabhu, Kandikere Ramaiah
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p. 9655 - 9668
(2015/01/16)
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- Novel benzoxazole inhibitors of mPGES-1
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A novel series of potent benzoxazole mPGES-1 inhibitors has been derived from a hit from a high throughput screen. Compound 37 displays mPGES-1 inhibition in an enzyme assay (0.018 μM) and PGE-2 inhibition in a cell-based assay (0.034 μM). It demonstrates 500- and 2500-fold selectivity for mPGES-1 over COX-2 and 6-keto PGF-1α, respectively. In vivo PK studies in dogs demonstrate 55% oral bioavailability and an 7 h half-life.
- Kablaoui, Natasha,Patel, Snahel,Shao, Jay,Demian, Douglas,Hoffmaster, Keith,Berlioz, Francioise,Vazquez, Michael L.,Moore, William M.,Nugent, Richard A.
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p. 907 - 911
(2013/02/25)
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- DERIVATIVES OF HETEROARYLSULFONAMIDES, THEIR PREPARATION AND THEIR APPLICATION IN HUMAN THERAPY
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The present invention concerns derivatives of heteroarylsulfonamides, notably as blockers of Kv potassium channels, and more particularly of channels Kv1.5, Kv4.3 or Kv11.1, their application in clinical therapy and their preparation methods. These compounds correspond to the following general formula (I): where R1 represents one or more substituents of the phenyl core X such as: hydrogen, halogen, trifluoromethyl, trifluoromethoxy, linear or branched C1-C4 alkyl, or linear or branched C1-C4 alkoxy, A represents oxygen or sulphur, B represents nitrogen when n=1 or 2 and D represents —C(═O)—, or B represents CH when n=0 and D represents —CH2O— or when n=1 and D represents —O—, R2 represents a hydrogen, a methyl, a fluorine or chlorine atom or a methoxy, HetAr represents a pyridyl or quinolyl group, possibly substituted by a group such as a linear or branched C1-C4 alkyl, a linear or branched C1-C4 alkoxy, a halogen, or a trifluoromethyl, and to their pharmaceutically acceptable salts.
- -
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Paragraph 0077; 0078; 0079; 0080
(2013/07/19)
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- Preparation, antibacterial evaluation and preliminary structure-activity relationship (SAR) study of benzothiazol- and benzoxazol-2-amine derivatives
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In this study, a novel benzothiazol- and benzooxazol-2-amine scaffold with antibacterial activity was designed and synthesized. Preliminary structure-activity relationship analysis displayed that compound 8t with a 5,6-difluorosubstituted benzothiazole was found to be a potent inhibitor of Gram-positive pathogens, and exhibited some potential against drug-resistant bacteria and without cytotoxicity in therapeutic concentrations. In addition, molecular docking studies indicated that Staphylococcus aureus methionyl-tRNA synthetase might be the possible target of these compounds. Taken together, the present study provides an effective entry to the synthesis of a good lead for subsequent optimization and a new small molecule candidate drug for antibacterial therapeutics.
- Ouyang, Liang,Huang, Yuhui,Zhao, Yuwei,He, Gu,Xie, Yongmei,Liu, Jie,He, Jun,Liu, Bo,Wei, Yuquan
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supporting information; experimental part
p. 3044 - 3049
(2012/06/04)
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- PROCESS FOR THE PREPARATION OF AN OREXIN RECEPTOR ANTAGONIST
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The present invention is directed to processes for preparing a diazepane compound which is an antagonist of orexin receptors, and which is useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is further directed to crystalline forms of this diazepane compound and pharmaceutical compositions thereof.
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Page/Page column 38
(2012/11/13)
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- DERIVATIVES OF HETEROARYLSULFONAMIDES, THEIR PREPARATION AND THEIR APPLICATION IN HUMAN THERAPY
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The present invention concerns derivatives of heteroarylsulfonamides, notably as blockers of Kv potassium channels, and more particularly of channels Kv1.5, Kv4.3 or Kv11.1, their application in clinical therapy and their preparation methods. These compounds correspond to the following general formula (I): where R1 represents one or more substituents of the phenyl core X such as: hydrogen, halogen, trifluoromethyl, trifluoromethoxy, linear or branched C1-C4 alkyl, or linear or branched C1-C4 alkoxy, A represents oxygen or sulphur, B represents nitrogen when n=1 or 2 and D represents ?C(=O)-, or B represents CH when n=0 and D represents ?CH2O? or when n=1 and D represents ?O?, R2 represents a hydrogen, a methyl, a fluorine or chlorine atom or a methoxy, HetAr represents a pyridyl or quinolyl group, possibly substituted by a group such as a linear or branched C1-C4 alkyl, a linear or branched C1-C4 alkoxy, a halogen, or a trifluoromethyl, and to their pharmaceutically acceptable salts.
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Page/Page column 18
(2012/06/15)
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- Analgesic Compounds, Compositions, and Uses Thereof
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The invention relates to compounds, compositions, and methods for diminishing pain in a subject in need thereof comprising administering the compounds and compositions herein described.
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Page/Page column 21
(2011/10/04)
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- PIPERIDINECARBOXAMIDES AS MPGES - 1 INHIBITORS
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The invention relates to piperidinecarboxamides of formula (I), to their use in medicine as mPGES-1 inhibitors for the treatment of pain, to compositions containing them, to processes for their preparation and to intermediates used in such processes.
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Page/Page column 34-35
(2011/07/09)
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- The first large-scale synthesis of MK-4305: A dual orexin receptor antagonist for the treatment of sleep disorder
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A new synthetic route to drug candidate 1, a potent and selective dual orexin antagonist for the treatment of sleep disorders, has been developed. The key acyclic precursor 10 was prepared in a one-step process in 75% isolated yield from commercially available starting materials using novel chemistry to synthesize 2-substituted benzoxazoles. A reductive amination was followed by a classical resolution to afford chiral diazepane (R)-11. Finally, coupling of (R)-11 with acid 5 furnished the desired drug candidate 1.
- Baxter, Carl A.,Cleator, Ed,Brands, Karel M. J.,Edwards, John S.,Reamer, Robert A.,Sheen, Faye J.,Stewart, Gavin W.,Strotman, Neil A.,Wallace, Debra J.
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experimental part
p. 367 - 375
(2012/05/19)
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- The first low μM SecA inhibitors
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SecA ATPase is a critical member of the Sec family, which is important in the translocation of membrane and secreted polypeptides/proteins in bacteria. Small molecule inhibitors can be very useful research tools as well as leads for future antimicrobial agent development. Based on previous virtual screening work, we optimized the structures of two hit compounds and obtained SecA ATPase inhibitors with IC50 in the single digit micromolar range. These represent the first low micromolar synthetic inhibitors of bacterial SecA and will be very useful for mechanistic studies.
- Chen, Weixuan,Huang, Ying-ju,Gundala, Sushma Reddy,Yang, Hsiuchin,Li, Minyong,Tai, Phang C.,Wang, Binghe
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experimental part
p. 1617 - 1625
(2010/05/17)
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- COMPOUNDS USEFUL AS FAAH MODULATORS AND USES THEREOF
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Compounds are disclosed that have formula I: wherein X, R1, R2, R3, R4 and n are as defined herein. The compounds and pharmaceutical compositions thereof are useful for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, anxiety, depression, inflammation, cognitive disorders, weight and eating disorders, Parkinson's disease, Alzheimer's disease, spasticity, addiction, glaucoma, and others.
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Page/Page column 48
(2010/04/27)
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- Discovery of 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2] nonane (CP-810,123), a novel α7 nicotinic acetylcholine receptor agonist for the treatment of cognitive disorders in schizophrenia: Synthesis, SAR development, and in vivo efficacy in cognition models
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A novel α7 nAChR agonist, 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4- diazabicyclo[3.2.2]nonane (24, CP-810,123), has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions including schizophrenia and Alzheimer's disease. Compound 24 is a potent and selective compound with excellent pharmaceutical properties. In rodent, the compound displays high oral bioavailability and excellent brain penetration affording high levels of receptor occupancy and in vivo efficacy in auditory sensory gating and novel object recognition. The structural diversity of this compound and its preclinical in vitro and in vivo package support the hypothesis that α7 nAChR agonists may have potential as a pharmacotherapy for the treatment of cognitive deficits in schizophrenia. 2009 American Chemical Society.
- O'Donnell, Christopher J.,Rogers, Bruce N.,Bronk, Brian S.,Bryce, Dianne K.,Coe, Jotham W.,Cook, Karen K.,Duplantier, Allen J.,Evrard, Edelweiss,Hajós, Mihaly,Hoffmann, William E.,Hurst, Raymond S.,Maklad, Noha,Mather, Robert J.,McLean, Stafford,Nedza, Frank M.,O'Neill, Brian T.,Peng, Langu,Qian, Weimin,Rottas, Melinda M.,Sands, Steven B.,Schmidt, Anne W.,Shrikhande, Alka V.,Spracklin, Douglas K.,Wong, Diane F.,Zhang, Andy,Zhang, Lei
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experimental part
p. 1222 - 1237
(2010/08/05)
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- DIAZEPANE COMPOUNDS WHICH MODULATE THE CB2 RECEPTOR
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Compounds of formula (I) are disclosed. Compounds according to the invention bind to and are agonists, antagonists or inverse agonists of the CB2 receptor, and are useful for treating inflammation. Those compounds which are agonists are additionally useful for treating pain.
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Page/Page column 38
(2009/05/30)
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- TRIAZOLE DERIVATIVES HAVING ANTIFUNGAL ACTIVITY, METHOD FOR THE PREPARATION THEREOF, AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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A triazole derivative of formula 1 or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof is superior to the conventional antifungal drugs in antifungal activity against a wide spectrum of pathogenic fungi, and has advantageously low toxicity.
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Page/Page column 29
(2009/01/24)
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- Regulatory molecules for the 5-HT3 receptor ion channel gating system
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Substituted benzoxazole derivatives which possess a nitrogen-containing heterocycle at C2 are selective partial agonists of the 5-HT3 receptor. Alteration of substituents on the benzoxazole nucleus affords both agonist-like and antagonist-like compounds, and uniquely modifies the function of the 5-HT3 receptor ion channel gating system. SAR and corroborative computational docking study for these partial agonists successfully explained structure and function of the 5-HT3 receptor.
- Yoshida, Satoshi,Watanabe, Takashi,Sato, Yasuo
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p. 3515 - 3523
(2008/02/07)
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- NOVEL PIPERAZINES, PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE THEREOF
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Disclosed are novel piperazine derivatives that act as agonists of the α7 nAChR. Also disclosed are phannaceutical compositions, methods of treating inflammatory conditions, methods of treating CNS disorders, methods for inhibiting cytokine release from mammalian cells and methods for the preparation of the novel compounds.
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Page/Page column 78-79
(2008/06/13)
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- Synthesis of benzoxazole-2-ones, benzothiazole-2-ones and their 2-thione derivatives: Efficient conversion of 2-thione to 2-oxo derivatives
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A highly practical procedure for preparing benzoxazole-2-ones, benzothiazole-2-ones and its 2-thione derivatives using ethylchloroformate and carbon disulfide and the corresponding aminophenols and aminothiophenols as the starting materials in one-pot protocol is presented. The yields vary from good to excellent, the conditions are mild, and the use of toxic and harmful chemicals is avoided. An efficient conversion of benzoxazole-2-thione to 2-one derivative in high yield has also been carried out.
- Singh,Singh, Pallavi,Singh, Shweta
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p. 1666 - 1671
(2008/09/19)
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- Synthesis and evaluation of arylaminoethyl amides as noncovalent inhibitors of cathepsin S. Part 3: Heterocyclic P3
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A series of Nα-2-benzoxazolyl-α-amino acid-(arylaminoethyl)amides were identified as potent, selective, and noncovalent inhibitors of cathepsin S. Structure-activity relationships including strategies for modulating the selectivities among cathepsins S, K, and L, and in vivo pharmacokinetics are discussed. A X-ray structure of compound 3 bound to the active site of cathepsin S is also reported.
- Tully, David C.,Liu, Hong,Alper, Phil B.,Chatterjee, Arnab K.,Epple, Robert,Roberts, Michael J.,Williams, Jennifer A.,Nguyen, Khanhlinh T.,Woodmansee, David H.,Tumanut, Christine,Li, Jun,Spraggon, Glen,Chang, Jonathan,Tuntland, Tove,Harris, Jennifer L.,Karanewsky, Donald S.
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p. 1975 - 1980
(2007/10/03)
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- Serotonin 5-HT3 receptor partial activator
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This invention provides a serotonin 5-HT3 receptor partial activator which has a serotonin 5-HT3 receptor activating action, in addition to its serotonin 5-HT3 receptor antagonism, and does not cause constipation as a side effect. Particularly, based on the finding that newly synthesized benzoxazole derivatives typified by the compounds of the following formula (2) have strong serotonin 5-HT3 receptor antagonism and serotonin 5-HT3 receptor activating action, this invention provides these benzoxazole derivatives as serotonin 5-HT3 receptor partial activators. In the above formula, R1 to R4 may be the same or different from one another and each represents a hydrogen atom, a halogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group or a substituted or unsubstituted amino group, or two groups of R1 and R2 may be linked together to form a ring structure, namely benzene ring; R5 represents a hydrogen atom, a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted lower alkenyl group; and m is an integer of 1 to 4.
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- Synthesis and reactivity of benzoxa(thia)zol-2-thiones: New route to 2- alkylthiobenzoxa(thia)zoles
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The reaction of aromatic primary amines 1 with carbon disulfide in the presence of a catalytic amount of triethylamine followed by treatment with aqueous hydrogen peroxide leads to the corresponding benzoxa-(thia)zol-2- thiones 3a-c which can be transformed with iminoethers into 2- alkylthiobenzoxa(thia)zoles 5a-h in good yields (64-85%). (C) 2000 Elsevier Science Ltd.
- Harizi, Abdallah,Romdhane, Anis,Mighri, Zine
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p. 5833 - 5835
(2007/10/03)
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- Benzoxazoline and benzimidazoline derivatives as novel aldose reductase inhibitors, part 1: Lead evolution
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Based on the 3D-pharmacophore model of aldose reductase inhibitors obtained by 3D-QSAR and protein-ligand docking study of spiroquinazolinones, we designed novel benzoxazoline and benzimidazoline derivatives. These compounds exhibited high potency enough to be promising as leads for further optimization.
- Nakao, Kazuya,Asao, Masaaki,Shirai, Hiroki,Saito, Kiyoshi,Moriya, Tamon,Iwata, Hiroshi,Matsumoto, Mamoru,Matsuoka, Yuzo,Shimizu, Ryo
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p. 621 - 630
(2007/10/03)
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- Benzoxazoline and benzimidazoline derivatives as novel aldose reductase inhibitors, part 2: Lead optimization
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We designed novel aldose reductase inhibitors, benzoxazoline and benzimidazoline derivatives, based on lead evolution from spiroquinazolinones. In order to optimize in vivo activity in the lens, variously substituted derivatives were synthesized. The relationship between structure and in vitro activity was also analyzed by comparative molecular field analysis. The optimized compound exhibited high potency in the lens.
- Nakao, Kazuya,Asao, Masaaki,Shirai, Hiroki,Saito, Kiyoshi,Moriya, Tamon,Iwata, Hiroshi,Matsumoto, Mamoru,Matsuoka, Yuzo,Shimizu, Ryo
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p. 631 - 642
(2007/10/03)
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- A new 5-HT3 receptor ligand. II. Structure-activity analysis of 5-HT3 receptor agonist action in the gut
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Several modified 2-piperazinyl benzoxazole derivatives, which exhibit an agonistic effect on gastrointestinal motility, were synthesized and their effects on the contraction of guinea-pig ileum were examined. The quaternary piperazinyl benzoxazole structure has a restricted conformation and stereostructure compared to those of the other 5-HT3 receptor agonists, serotonin and meta-chlorophenylbiguanide. The mutual positions of the aromatic ring, nitrogen atom and terminal amine are considered to form the pharmacophore of the 5-HT3 receptor agonist in the gut. In the serotonin- evoked reflex bradycardia [Bezold-Jarisch (B-J) reflex] inhibition test using rats the B-J reflex-inducing ratio was different for each synthesized compound. These results suggest that, in these 5-HT3 receptor agonists, the substituents of the benzoxazole ring influence the B-J reflex-inducing activity in rats.
- Yamada, Megumi,Sato, Yasuo,Kobayashi, Kazuko,Konno, Fukio,Soneda, Tomoko,Watanabe, Takashi
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p. 445 - 451
(2007/10/03)
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- Benzoxazole derivatives as novel 5-HT3 receptor partial agonists in the gut
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A series of benzoxazoles with a nitrogen-containing heterocyclic substituent at the 2-position was prepared and evaluated for 5-HT3 partial agonist activity on isolated guinea pig ileum. The nature of the substituent at the 5-position of the benzoxazole ring affected the potency for the 5-HTs receptor, and the 5-chloro derivatives showed increased potency and lowered intrinsic activity. 5-Chloro-7-methyl-2-(4-methyl-1- homopiperazinyl)benzoxazole (6v) exhibited a high binding affinity in the same range as that of the 5-HT3 antagonist granisetron, and its intrinsic activity was 12% of that of 5-HT. Compound 6v inhibited 5-HT-evoked diarrhea but did not prolong the transition time of glass beads in the normal distal colon even at a dose of 100 times the ED50 for diarrhea inhibition in mice. Compounds of this type are expected to be effective for the treatment of irritable bowel syndrome without the side effect of constipation.
- Sato, Yasuo,Yamada, Megumi,Yoshida, Satoshi,Soneda, Tomoko,Ishikawa, Midori,Nizato, Tetsutaro,Suzuki, Kokichi,Konno, Fukio
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p. 3015 - 3021
(2007/10/03)
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- Facile rearrangements of alkynylamino heterocycles with noble metal cations
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A number of 2-(alkynylamino)-substituted heterocycles have been synthesized. These heterocycles rearrange in the presence of silver(I) and gold(I) salts to give novel 2H-pyrimido[2,1-b]benzoxazoles, 2H-pyrimido[2,1-b]benzothiazoles, and a 2H-pyrimido[2,1-b]benzoselenazole. Two of the the 2H-pyrimido[2,1-b]benzoxazoles were isolated in good yield. The kinetics of the silver tetrafluoroborate-catalyzed rearrangements of selected (alkynylamino)benzoxazoles and benzothiazoles have been examined by 1H NMR in CD3CN. Factors affecting the electron densities of the triple bond and of the nitrogen atom in the heterocycle are important in influencing the rate of rearrangement.
- Lok, Roger,Leone, Ronald E.,Williams, Antony J.
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p. 3289 - 3297
(2007/10/03)
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- Benzoxazolamines and Benzothiazolamines: Potent, Enantioselective Inhibitors of Leukotriene Biosynthesis with a Novel Mechanism of Action
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A series of benzoxazolamine and benzothiazolamine analogs that inhibit leukotriene (LT) biosynthesis are described.The initial lead, (S)-N-(benzothiazol-2-yl)phenylalanine ethyl ester (5a), was discovered in a screening program for inhibition of Ca-ionophore-A23187-induced LTB4 release in human polymorphonuclear leukocytes (IC50 0.23 μM).Through structural modification, it was determined that hydrophobic substituents in the 5-position and replacement of the phenyl ring of phenylalanine with a cyclohexyl group greatly enhance potency.Several ester bioisosteres that retain potency and enantiomeric selectivity are described.Lead optimization culminated in (S)-N--5-methyl-2-benzoxazolamine (43b), IC50 0.001 μM.The compounds described are not inhibitors of 5-lipoxygenase but, rather, act at the level of arachidonic acid release.
- Lazer, Edward S.,Miao, Clara K.,Wong, Hin-Chor,Sorcek, Ronald,Spero, Denice M.,et al.
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p. 913 - 923
(2007/10/02)
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- 3-[1-(2-Benzoxazolyl)hydrazino]propanenitrile derivatives: Inhibitors of immune complex induced inflammation
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3-[1-(2-Benzoxazolyl)hydrazino]propanenitrile derivatives were evaluated in the dermal and pleural reverse passive Arthus reactions in the rat. In the pleural test these compounds were effective in reducing exudate volume and accumulation of white blood cells. This pattern of activity was similar to that of hydrocortisone and different from that of indomethacin. The structural requirements for inhibiting the Arthus reactions were studied by systematic chemical modification of 1. These structure-activity relationship studies revealed that nitrogen 1' of the hydrazino group is essential for activity and must be electron rich, whereas chemical modifications of other sites of 1 had only a modest effect on activity.
- Haviv,Ratajczyk,DeNet,Kerdesky,Walters,Schmidt,Holms,Young,Carter
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p. 1719 - 1728
(2007/10/02)
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- Process for the preparation of halo-2-mercaptobenzoxazoles
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Preparation of 5- and 6-halo-2-mercaptobenzoxazoles or the sodium and potassium salts thereof by reaction of corresponding 4- or 5-halo-2-aminophenols with sodium or potassium lower alkyl xanthates in heterogeneous phase.
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