- Synthesis and structure-activity relationships of new 2-phenoxybenzamides with antiplasmodial activity
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The 2-phenoxybenzamide 1 from the Medicines for Malaria Venture Malaria Box Project has shown promising multi-stage activity against different strains of P. falciparum. It was successfully synthesized via a retrosynthetic approach. Subsequently, twenty-one new derivatives were prepared and tested for their in vitro activity against blood stages of the NF54 strain of P. falciparum. Several insights into structure-activity relationships were revealed. The antiplasmodial activity and cytotoxicity of compounds strongly depended on the substitution pattern of the anilino partial structure as well as on the size of substituents. The diaryl ether partial structure had further impacts on the activity. Additionally, several physicochemical and pharmacokinetic parameters were calculated (log P, log D7.4 and ligand efficiency) or determined experimentally (passive permeability and CYP3A4 inhibition). The tert-butyl-4-{4-[2-(4-fluorophenoxy)-3-(trifluoromethyl)benzamido]phenyl}piperazine-1-carboxylate possesses high antiplasmodial activity against P. falciparum NF54 (PfNF54 IC50 = 0.2690 μM) and very low cytotoxicity (L-6 cells IC50 = 124.0 μM) resulting in an excellent selectivity index of 460. Compared to the lead structure 1 the antiplasmodial activity was improved as well as the physicochemical and some pharmacokinetic parameters.
- Dolensky, Johanna,Hermann, Theresa,Hochegger, Patrick,Kaiser, Marcel,M?ser, Pascal,Pferschy-Wenzig, Eva-Maria,Saf, Robert,Seebacher, Werner,Weis, Robert
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- PYRROLE mTORC INHIBITORS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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- A class of GPR40 agonist compounds with amide structure, and uses thereof
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The present invention relates to a class of amide compounds with a novel structure, and a pharmaceutical composition thereof, wherein the structure of the amide compound is represented by a general formula (I). According to the present invention, the amide compound (I) can regulate GPR40 activity, and can be used for GPR40 activity related diseases such as diabetes and metabolic syndrome. The formula I is defined in the specification.
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Paragraph 0145; 0146; 0147; 0148; 0151
(2019/05/02)
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- COMPOUND SUITABLE FOR DETECTION OF VESICULAR ACETYLCHOLINE TRANSPORTER
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PROBLEM TO BE SOLVED: To provide a compound suitable for detection of vesicular acetylcholine transporter which can be also used as a compound labeled in PET method. SOLUTION: The present invention provides a compound represented by formula (I), where Rs
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Paragraph 0049; 0050
(2018/09/27)
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- PYRROLE mTORC INHIBITORS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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- NEW VORTIOXETINE INTERMEDIATE AND SYNTHESIS PROCESS THEREOF
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The present invention provides a new intermediate II and a method for synthesizing the same. The method comprises: (a) firstly diazotizing a compound of formula I as a raw material, and then halogenating to obtain an intermediate II; and (b) reacting the
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Paragraph 0032-0033
(2017/04/12)
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- Suitable for vesicle acetylecholine translocator detection compound (by machine translation)
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The present invention provides a compound represented by formula (I), wherein in formula (I), R 1 represents CH 3 , F, (CH 2 ) n -F, NH-(CH 2 ) n -F, O-(CH 2 ) n -F or S-(CH 2 ) n -F, and n represents an integer of 1 to 3.
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Paragraph 0073; 0074; 0075; 0076; 0077
(2016/10/07)
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- SYNTHESIS OF VORTIOXETINE VIA (2-(PIPERAZINE-1 -YL)PHENYL)ANILINE INTERMEDIATES
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The present invention provides a new synthetic process for the production of 1-(2-((2,4- dimethylphenyl)thio)phenyl)piperazine (vortioxetine), a drug for the treatment of depression and anxiety, which is conducted via (2-(piperazine-1-yl)phenyl)aniline intermediates.
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Page/Page column 14
(2015/08/03)
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- Synthesis of vortioxetine via (2-(piperazine-1-yl)phenyl)aniline intermediates
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The present invention provides a new synthetic process for the production of 1-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine (vortioxetine), a drug for the treatment of depression and anxiety, which is conducted via (2-(piperazine-1-yl)phenyl)aniline intermediates.
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Paragraph 0038; 0039
(2015/07/22)
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- PIM KINASE INHIBITORS AND METHODS OF THEIR USE
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New compounds, compositions and methods of inhibition of kinase activity associated with tumorigenesis in a human or animal subject are provided. In certain embodiments, the compounds and compositions are effective to inhibit the activity of at least one serine/threonine kinase or receptor tyrosine kinase. The new compounds and compositions may be used either alone or in combination with at least one additional agent for the treatment of a serine/threonine kinase- or receptor tyrosine kinase- mediated disorder, such as cancer.
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Page/Page column 47
(2008/12/07)
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- Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT 6 receptor antagonists
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Starting from the potent and selective but poorly brain penetrant 5-HT 6 receptor antagonist SB-271046, a successful strategy for improving brain penetration was adopted involving conformational constraint with concomitant reduction in hydrogen bond count. This provided a series of bicyclic heteroarylpiperazines with high 5-HT6 receptor affinity. 5-Chloroindole 699929 combined high 5-HT6 receptor affinity with excellent brain penetration and also had good oral bioavailability in both rat and dog.
- Ahmed, Mahmood,Briggs, Michael A.,Bromidge, Steven M.,Buck, Tania,Campbell, Lorraine,Deeks, Nigel J.,Garner, Ashley,Gordon, Laurie,Hamprecht, Dieter W.,Holland, Vicky,Johnson, Christopher N.,Medhurst, Andrew D.,Mitchell, Darren J.,Moss, Stephen F.,Powles, Jenifer,Seal, Jon T.,Stean, Tania O.,Stemp, Geoffrey,Thompson, Mervyn,Trail, Brenda,Upton, Neil,Winborn, Kim,Witty, David R.
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p. 4867 - 4871
(2007/10/03)
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- Synthesis and Structure-Activity Relationships of Novel Arylpiperazines as Potent and Selective Agonists of the Melanocortin Subtype-4 Receptor
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The melanocortin receptors have been implicated as potential targets for a number of important therapeutic indications, including inflammation, sexual dysfunction, and obesity. We identified compound 1, an arylpiperazine attached to the dipeptide H-D-Tic-D-p-Cl-Phe-OH, as a novel melanocortin subtype-4 receptor (MC4R) agonist through iterative directed screening of nonpeptidyl G-protein-coupled receptor biased libraries. Structure-activity relationship (SAR) studies demonstrated that substitutions at the ortho position of the aryl ring improved binding and functional potency. For example, the o-isopropyl-substituted compound 29 (Ki = 720 nM) possessed 9-fold better binding affinity compared to the unsubstituted aryl ring (Ki = 6600 nM). Sulfonamide 39 (Ki = 220 nM) fills this space with a polar substituent, resulting in a further 2-fold improvement in binding affinity. The most potent compounds such as the diethylamine 44 (Ki = 60 nM) contain a basic group at this position. Basic heterocycles such as the imidazole 50 (Ki = 110 nM) were similarly effective. We also demonstrated good oral bioavailability for sulfonamide 39.
- Richardson, Timothy I.,Ornstein, Paul L.,Briner, Karin,Fisher, Matthew J.,Backer, Ryan T.,Biggers, C. Kelly,Clay, Michael P.,Emmerson, Paul J.,Hertel, Larry W.,Hsiung, Hansen M.,Husain, Saba,Kahl, Steven D.,Lee, Jonathan A.,Lindstrom, Terry D.,Martinelli, Michael J.,Mayer, John P.,Mullaney, Jeffery T.,O'Brien, Thomas P.,Pawlak, Joseph M.,Revell, Kevin D.,Shah, Jikesh,Zgombick, John M.,Herr, R. Jason,Melekhov, Alex,Sampson, Peter B.,King, Chi-Hsin R.
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p. 744 - 755
(2007/10/03)
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- Aryl piperazine melanocortin MC4 receptor agonists
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Incorporation of substituted phenyl piperazine privileged structures into a known MC4 specific dipeptoid consensus sequence resulted in a series of potent (EC50=24 nM) and selective MC4-R agonists. We report the SAR of this series of compounds
- Dyck, Brian,Parker, Jessica,Phillips, Teresa,Carter, Lee,Murphy, Brian,Summers, Robin,Hermann, Julia,Baker, Tracy,Cismowski, Mary,Saunders, John,Goodfellow, Val
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p. 3793 - 3796
(2007/10/03)
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- Synthesis of new quinoxaline derivatives by reductive cyclization of various 1-(2-nitrophenyl)-2-cyanoamines
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The electrochemical cyanation of various six-membered N-(2-nitrophenyl) heterocyclic amines, including piperidine, morpholine, thiomorpholine, and N-Boc-protected piperazine derivatives, was investigated. The expected cyanoamines 5 were obtained in good y
- Renaud, Tristan,Hurvois, Jean-Pierre,Uriac, Philippe
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p. 987 - 996
(2007/10/03)
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- Solution phase combinatorial synthesis of arylpiperazines
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A solution phase combinatorial synthesis of aryl piperazines 1 and 2 is described based on the S(N)Ar reaction and Schotten-Baumann acylation. The use of excess reagent is allowed and pure arylpiperazines 1 and 2 were obtained by simple acid/base washing.
- Neuville, Luc,Zhu, Jieping
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p. 4091 - 4094
(2007/10/03)
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