- Novel acyl-CoA: Cholesterol acyltransferase inhibitor: Indoline-based sulfamide derivatives with low lipophilicity and protein binding ratio
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To find a novel acyl-CoA: cholesterol acyltransferase inhibitor, a series of sulfamide derivatives were synthesized and evaluated. Compound 1d, in which carboxymethyl moiety at the 5-position of Pactimibe was replaced by a sulfamoylamino group, showed 150-fold more potent anti-foam cell formation activity (IC50: 0.02 μM), 1.6-fold higher log D7.0 (4.63), and a slightly lower protein binding ratio (93.2%) than Pactimibe. Compound 1i, in which the octyl chain at the 1-position in 1d was replaced by an ethoxyethyl, showed markedly low log D7.0 (1.73) and maintained 3-fold higher anti-foam cell formation activity (IC50: 1.0 μM), than Pactimibe. The plasma protein binding ratio (PBR) of 1i was much lower than that of Pactimibe (62.5% vs. 98.1%), and its partition ratio to the rabbit atherosclerotic aorta after oral administration was higher than that of Pactimibe. Compound 1i at 10 μM markedly inhibited cholesterol esterification in atherosclerotic rabbit aortas even when incubated with serum, while Pactimibe had little effect probably due to its high PBR. In conclusion, compound 1i is expected to more efficiently inhibit the progression of atherosclerosis than Pactimibe.
- Takahashi, Kenji,Ohta, Masaru,Shoji, Yoshimichi,Kasai, Masayasu,Kunishiro, Kazuyoshi,Miike, Tomohiro,Kanda, Mamoru,Shirahas, Hiroaki
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Read Online
- 4-Chlorobenzyl sulfonamide and sulfamide derivatives of histamine homologues: The design of potent histamine H3 receptor antagonists
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4-Chlorophenylmethanesulfonamide and (4-chlorobenzyl)sulfamide derivatives of histamine homologues were prepared and found to be potent and selective histamine H3 receptor antagonists. High receptor affinity and low differences in the data from the bioassays were achieved with the imidazol-4-ylbutyl analogues.
- Tozer, Matthew J.,Buck, Ildiko M.,Cooke, Tracey,Barret Kalindjian,McDonald, Iain M.,Pether, Michael J.,Steel, Katherine I. M.
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Read Online
- N,N′-substituted 1,2,5 thiadiazolidine 1,1-dioxides: Synthesis, selected chemical and spectral proprieties and antimicrobial evaluation
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The sulfamide functional group is increasingly relevant in both medicinal and bioorganic chemistry. We report here practical access to a series of N2,N5-substituted five-membered cyclosulfamides. The five-membered heterocyclic motif was prepared starting from proteogenic amino acids and chlorosulfonyl isocyanate via the Mitsunobu reaction. Selected chemical and spectral proprieties and the antimicrobial evaluation of these compounds are detailed.
- Bendjeddou, Amel,Djeribi, Ryad,Regainia, Zine,Aouf, Nour-Eddine
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Read Online
- Synthesis and evaluation of sulfamide-type indolizidines as glycosidase inhibitors
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A practical synthesis of reducing sulfamide-derived iminosugar glycomimetics related to the indolizidine glycosidase inhibitor family is reported. The polyhydroxylated bicyclic system was built from readily accessible hexofuranose derivatives through a sy
- Benltifa, Mahmoud,Garcia Moreno, M. Isabel,Ortiz Mellet, Carmen,Garcia Fernandez, Jose M.,Wadouachi, Anne
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Read Online
- Direct synthesis of Z, BOC, FMOC, ALLOC... Derivatives of 5- aminooxazoles starting from acylamino acids and chlorosulfonylcarbamates
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A one-step synthesis of 5-oxazolecarbamates 1-11 can be easily carried out starting from N-acetylated and benzoylated aminoacids such as Gly, Ala, Leu, Phe, and chlorosulfonyl carbamates, prepared in situ by addition of alcohols on chlorosulfonyl isocyanate (CSI). The structure of the compounds was confirmed by X-Ray crystallography. A subsequent exocyclic N-alkylation gave substituted 12. 18 derivatives. Carbamate cleavage gave by spontaneous reopening substituted N-acylaminoamides, in excellent yields.
- Dewynter, Georges,Hajri, A. Houssem,Toupet, Loic,Montero, Jean-Louis
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Read Online
- Diversely substituted sulfamides for fragment-based drug discovery of carbonic anhydrase inhibitors: synthesis and inhibitory profile
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A series of sulfamide fragments has been synthesised and investigated for human carbonic anhydrase inhibition. One of the fragments showing greater selectivity for cancer-related isoforms hCA IX and XII was co-crystalized with hCA II showing significant potential for fragment periphery evolution via fragment growth and linking. These opportunities will be identified in the future via the screening of this fragment structure for co-operative carbonic anhydrase binding with other structurally diverse fragments.
- Angeli, Andrea,Ferraroni, Marta,Kalinin, Stanislav,Korsakov, Mikhail,Krasavin, Mikhail,Nocentini, Alessio,Sharonova, Tatiana,Supuran, Claudiu T.,Zhmurov, Petr
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p. 857 - 865
(2022/03/27)
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- Potential antibacterial and antifungal activities of novel sulfamidophosphonate derivatives bearing the quinoline or quinolone moiety
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A series of new α-sulfamidophosphonate/sulfonamidophosphonate (4a–n) and cyclosulfamidophosphonate (5a–d) derivatives containing the quinoline or quinolone moiety was designed and synthesized via Kabachnik–Fields reaction in the presence of ionic liquid under ultrasound irradiation. This efficient methodology provides new 1,2,5-thiadiazolidine-1,1-dioxide derivatives 5a–d in one step and optimal conditions. The molecular structures of the novel compounds 4a–n and 5a–d were confirmed using various spectroscopic methods. All these compounds were evaluated for their in vitro antibacterial activity against Gram-negative (Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853) and Gram-positive (Staphylococcus aureus ATCC 27923) bacteria, in addition to three clinical strains (E. coli 1, P. aeruginosa 1, and S. aureus 1). Most of the tested compounds showed more potent inhibitory activities against both Gram-positive and -negative bacteria compared with the sulfamethoxazole reference. The following compounds, 4n, 4f, 4g, 4m, 4l, 4d, and 4e, are the most active sulfamidophosphonate derivatives. Furthermore, these molecules gave interesting zones of inhibition varying between 28 and 49 mm, against all tested bacterial strains, with a low minimum inhibitory concentration (MIC) value ranging from 0.125 to 8 μg/ml. All the synthesized derivatives were also evaluated for their in vitro antifungal activity against Fusarium oxyporum f. sp. lycopersici and Alternaria sp. The results revealed that all the synthesized compounds exhibited excellent antifungal inhibition and the compounds 4f, 4g, 4m, and 4i were the most potent derivatives with MIC values ranging from 0.25 to 1 μg/ml against the two tested fungal strains. The strongest inhibition of bacteria and fungi strains was detected by the effect of quinolone and sulfamide moieties.
- Bazine, Ismahene,Bendjedid, Samira,Boukhari, Abbes
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- Development of sulfahydantoin derivatives as β-lactamase inhibitors
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Sulfahydantoin-based molecules may provide a means to counteract antibiotic resistance, which is on the rise. These molecules may act as inhibitors of β-lactamase enzymes, which are key in some resistance mechanisms. In this paper, we report on the synthe
- Paquet-C?té, Pierre-Alexandre,Alejaldre, Lorea,Lapointe Verreault, Camille,Gobeil, Sophie M.C.,Lamoureux, Rosalie,Bédard, Laurie,Normandeau, Charles-Olivier,Lemay-St-Denis, Claudèle,Pelletier, Joelle N.,Voyer, Normand
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supporting information
(2021/01/25)
-
- Exploiting the Tolerant Region i of the Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Binding Pocket: Discovery of Potent Diarylpyrimidine-Typed HIV-1 NNRTIs against Wild-Type and E138K Mutant Virus with Significantly Improved Water Solubility an
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Diarylpyrimidine derivatives (DAPYs) exhibit robust anti-HIV-1 potency, although they have been compromised by E138K variant and severe side-effects and been suffering from poor water solubility. In the present work, hydrophilic morpholine or methylsulfon
- Huang, Boshi,Chen, Wenmin,Zhao, Tong,Li, Zhenyu,Jiang, Xiangyi,Ginex, Tiziana,Vílchez, David,Luque, Francisco Javier,Kang, Dongwei,Gao, Ping,Zhang, Jian,Tian, Ye,Daelemans, Dirk,De Clercq, Erik,Pannecouque, Christophe,Zhan, Peng,Liu, Xinyong
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p. 2083 - 2098
(2019/03/07)
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- PROTEIN KINASE MKK4 INHIBITORS FOR PROMOTING LIVER REGENERATION OR REDUCING OR PREVENTING HEPATOCYTE DEATH
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The invention relates to pyrazolo-pyridine compounds which inhibit mitogen-activated protein kinase kinase 4 (MKK4) and in particular, selectively inhibit MKK4 over protein kinases JNK1 and MKK7. The compounds are useful for promoting liver regeneration or reducing or preventing hepatocyte death. They are further useful for treating osteoarthritis or rheumatoid arthritis, or CNS-related diseases.
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Page/Page column 91
(2019/08/26)
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- HETEROARYLDIHYDROPYRIMIDINE DERIVATIVES AND METHODS OF TREATING HEPATITIS B INFECTIONS
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Provided herein are compounds useful for the treatment of HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in the subject.
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Page/Page column 107
(2019/01/17)
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- BETA-LACTAMASE INHIBITOR COMPOUNDS
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The present invention is directed to compounds which are beta-lactamase inhibitors. The compounds and their pharmaceutically acceptable salts are useful in combination with beta- lactam antibiotics, for the treatment of bacterial infections, including infections caused by drug resistant organisms, including multi-drug resistant organisms. The present invention includes compounds according to Formula (I): or a pharmaceutically acceptable salt thereof, wherein the values of R1, R2, R3, R4, R5 and R6 are described herein.
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Page/Page column 180
(2018/04/13)
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- SULFONYL UREA DERIVATIVES AND THEIR USE IN THE CONTROL OF INTERLEUKIN-1 ACTIVITY
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The present invention relates to compounds of Formula (I) and to their pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein inhibit the maturation of cytokines of the IL-1 family by inhibiting inflammasomes and may be used in the treatment of disorders in which inflammasome activity is implicated, such as inter alia autoinflammatory and autoimmune diseases.
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Page/Page column 70
(2018/02/17)
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- MACROCYCLIC BROAD SPECTRUM ANTIBIOTICS
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Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.
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Paragraph 001057; 001059
(2018/09/12)
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- COMPOUNDS AND METHODS FOR TREATING BACTERIAL INFECTIONS
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Provided herein are antibacterial compounds represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X, Y, R4, R5, and R6 are as defined herein. Also provided are pharmaceutical compositions compris
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Paragraph 00114
(2018/12/03)
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- SULFAMATE DERIVATIVE COMPOUNDS, PROCESSES FOR PREPARING THEM AND THEIR USES
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The present invention relates to a pharmaceutical composition for treating or preventing CNS disorders containing a sulfamate derivative compound and/or pharmaceutically acceptable salt thereof as an active ingredient. Furthermore, the present invention relates to a method for treatment or prevention CNS disorders comprising administering a sulfamate derivative compound in a pharmaceutically effective amount to a subject in need of treatment or prevention of CNS disorders.
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Page/Page column 36
(2017/09/15)
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- INCB24360 (Epacadostat), a Highly Potent and Selective Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitor for Immuno-oncology
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A data-centric medicinal chemistry approach led to the invention of a potent and selective IDO1 inhibitor 4f, INCB24360 (epacadostat). The molecular structure of INCB24360 contains several previously unknown or underutilized functional groups in drug subs
- Yue, Eddy W.,Sparks, Richard,Polam, Padmaja,Modi, Dilip,Douty, Brent,Wayland, Brian,Glass, Brian,Takvorian, Amy,Glenn, Joseph,Zhu, Wenyu,Bower, Michael,Liu, Xiangdong,Leffet, Lynn,Wang, Qian,Bowman, Kevin J.,Hansbury, Michael J.,Wei, Min,Li, Yanlong,Wynn, Richard,Burn, Timothy C.,Koblish, Holly K.,Fridman, Jordan S.,Emm, Tom,Scherle, Peggy A.,Metcalf, Brian,Combs, Andrew P.
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supporting information
p. 486 - 491
(2017/05/19)
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- Selective IKur Inhibitors for the Potential Treatment of Atrial Fibrillation: Optimization of the Phenyl Quinazoline Series Leading to Clinical Candidate 5-[5-Phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide
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We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent IKur current blocker with selectivity versus hERG, Na and Ca channels, and an acceptable preclinical PK profile. Upon further characterization in vivo, compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2′ position for a series of close analogues by employing hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide (25) was identified as the lead compound in this series. Compound 25 showed robust effects in rabbit and canine pharmacodynamic models and an acceptable cross-species pharmacokinetic profile and was advanced as the clinical candidate. Further optimization of 25 to mitigate pH-dependent absorption resulted in identification of the corresponding phosphoramide prodrug (29) with an improved solubility and pharmacokinetic profile.
- Gunaga, Prashantha,Lloyd, John,Mummadi, Somanadham,Banerjee, Abhisek,Dhondi, Naveen Kumar,Hennan, James,Subray, Veena,Jayaram, Ramya,Rajugowda, Nagendra,Umamaheshwar Reddy, Kommuri,Kumaraguru, Duraimurugan,Mandal, Umasankar,Beldona, Dasthagiri,Adisechen, Ashok Kumar,Yadav, Navnath,Warrier, Jayakumar,Johnson, James A.,Sale, Harinath,Putlur, Siva Prasad,Saxena, Ajay,Chimalakonda, Anjaneya,Mandlekar, Sandhya,Conder, MaryLee,Xing, Dezhi,Gupta, Arun Kumar,Gupta, Anuradha,Rampulla, Richard,Mathur, Arvind,Levesque, Paul,Wexler, Ruth R.,Finlay, Heather J.
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supporting information
p. 3795 - 3803
(2017/05/19)
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- Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures
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Target-based approaches toward new antimalarial treatments are highly valuable to prevent resistance development. We report several series of pyrazolopyran-based inhibitors targeting the enzyme serine hydroxymethyltransferase (SHMT), designed to improve microsomal metabolic stability and to identify suitable candidates for in vivo efficacy evaluation. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target assays and PfNF54 strains in cell-based assays with values in the low nanomolar range (3.2-55 nM). A set of carboxylate derivatives demonstrated markedly improved in vitro metabolic stability (t1/2 > 2 h). A selected ligand showed significant in vivo efficacy with 73% of parasitemia reduction in a mouse model. Five new cocrystal structures with PvSHMT were solved at 2.3-2.6 ? resolution, revealing a unique water-mediated interaction with Tyr63 at the end of the para-Aminobenzoate channel. They also displayed the high degree of conformational flexibility of the Cys364-loop lining this channel.
- Schwertz, Geoffrey,Witschel, Matthias C.,Rottmann, Matthias,Bonnert, Roger,Leartsakulpanich, Ubolsree,Chitnumsub, Penchit,Jaruwat, Aritsara,Ittarat, Wanwipa,Sch?fer, Anja,Aponte, Raphael A.,Charman, Susan A.,White, Karen L.,Kundu, Abhijit,Sadhukhan, Surajit,Lloyd, Mel,Freiberg, Gail M.,Srikumaran, Myron,Siggel, Marc,Zwyssig, Adrian,Chaiyen, Pimchai,Diederich, Fran?ois
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supporting information
p. 4840 - 4860
(2017/06/28)
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- BIOCONJUGATES CONTAINING SULFAMIDE LINKERS FOR USE IN TREATMENT
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The present invention is based on the surprising finding that the linker employed in a bioconjugate, such as an anti-body-drug conjugate, is not therapeutically inert but has an effect on the therapeutic index of the bioconjugate. The present invention thus concerns a method for increasing the therapeutic index of a bioconjugate and the bioconjugates for use in treatment, in particular cancer. The bioconjugates according to the invention have a sulfamide linker comprising a group according to formula (1).
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Page/Page column 64; 65
(2017/09/05)
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- HETEROARYL COMPOUNDS USEFUL AS INHIBITORS OF SUMO ACTIVATING ENZYME
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Disclosed are chemical entities which are compounds of formula (I); or pharmaceutically acceptable salts thereof; wherein Y, Ra, Ra', Rb, Rc, X1, X2, X3, Rd, Z1, and Z2 have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry. Chemical entities according to the disclosure can be useful as inhibitors of Sumo Activating Enzyme (SAE). Further provided are pharmaceutical compositions comprising a compound of the disclosure and methods of using the compositions in the treatment of proliferative, inflammatory, cardiovascular, and neurodegenerative diseases or disorders.
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Paragraph 001025
(2016/01/25)
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- Synthesis and antitumor evaluation of novel sulfonylcycloureas derived from nitrogen mustard
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A new series of sulfonylcycloureas derivatives have been synthesized and evaluated in vitro for their antitumor activity against four cancer cell lines (A431, Jurkat, U266, and K562). These compounds were prepared by the condensation of several sulfonamides (2am) with ethyl bis(2-chloroethyl)carbamate (1a). The relative cytotoxicity of these new derivatives in comparison to chlorambucil is reported.
- Cheloufi,Belhani,Ouk,Zerrouki,Aouf,Berredjem
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p. 399 - 405
(2016/04/20)
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- Intramolecular oxidative palladium-catalyzed diamination reactions of alkenyl sulfamates: An efficient synthesis of [1,2,5]thiadiazolo-fused piperazinones
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A palladium-catalyzed diamination domino process of sulfamates arising from glycine allylamides is reported. The reaction leads to the formation of [1,2,5]thiadiazolo-fused piperazinones. The essential feature of the synthetic route is the use of PdCl2(MeCN)2/CuBr2, as a catalytic system which promotes the second amination process, leading to the bicycle ring-fused compounds in good yields.
- Chiacchio, Ugo,Broggini, Gianluigi,Romeo, Roberto,Gazzola, Silvia,Chiacchio, Maria A.,Giofrè, Salvatore V.,Gabriele, Bartolo,Mancuso, Raffaella,Floresta, Giuseppe,Zagni, Chiara
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p. 57521 - 57529
(2016/07/06)
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- 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase
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The present invention is directed to 1,2,5-oxadiazole derivatives, and compositions of the same, which are inhibitors of indoleamine 2,3-dioxygenase and are useful in the treatment of cancer and other disorders, and to the processes and intermediates for making such 1,2,5-oxadiazole derivatives.
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Page/Page column 42
(2016/05/24)
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- SULFAMIDE LINKER, CONJUGATES THEREOF, AND METHODS OF PREPARATION
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The present invention relates to a compound comprising an alpha-end and an omega-end, the compound comprising on the alpha-end a reactive group Qlcapable of reacting with a functional group F1present on a biomolecule and on the omega-end a target molecule, the compound further comprising a group according to formula (1) or a salt thereof: Said compound may also be referred to as a linker-conjugate. The invention also relates to a process for the preparation of a bioconjugate, the process comprising the step of reacting a reactive group Q1of a linker-conjugate according to the invention with a functional group F1of a biomolecule. The invention further relates to a bioconjugate obtainable by the process according to the invention. In a preferred embodiment, the invention concerns a process for the preparation of a bioconjugate via a cycloaddition, such as a (4+2)-cycloaddition (e.g. a Diels-Alder reaction) or a (3+2)-cycloaddition (e.g. a 1,3-dipolar cycloaddition).
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Page/Page column 100
(2016/04/26)
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- ARGINASE INHIBITORS AND THEIR THERAPEUTIC APPLICATIONS
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The inventive compounds are small molecule therapeutics that are potent inhibitors of arginase 1 and arginase 2 activity. The inventions also provides pharmaceutical compositions and methods for using the inventive compounds for treating or preventing a disease or condition associated with arginase activity.
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Page/Page column 49; 75
(2016/07/27)
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- FUSED-RING COMPOUNDS, PHARMACEUTICAL COMPOSITION AND USES THEREOF
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This disclosure is related to a fused-ring compound of formula (I) and/or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the fused ring compound of formula (I) and/or a pharmaceutically acceptable salt thereof, preparation methods thereof, and use thereof in modulating activity of indoleamine 2, 3-dioxygenase (IDO) and/or tryptophan 2, 3-dioxygenase (TDO). This disclosure further provides methods of treating IDO and/or TDO-associated diseases, including cancer, viral infection and autoimmune diseases.
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Paragraph 697; 698; 699
(2016/09/15)
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- Amino sulfonyl compound, preparation method and uses thereof
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The present invention relates to a new amino sulfonyl compound represented by a general formula I, or a tautomer, an enantiomer, a racemate or a pharmaceutically acceptable salt thereof, a preparation method, a pharmaceutical composition, and uses thereof, wherein the compound can be used for treatment of epilepsy, convulsion, obesity, and the like. The general formula I is defined in the specification.
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Paragraph 0145; 0146
(2016/12/01)
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- INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS REPLICATION
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Compounds of Formula I, including pharmaceutically acceptable salts thereof, and compositions and methods for treating human immunodeficiency virus (HIV) infection are set forth: (I)
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Page/Page column 77
(2016/11/14)
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- PROCESS FOR THE SYNTHESIS OF AN INDOLEAMINE 2,3-DIOXYGENASE INHIBITOR
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The present application is directed to processes and intermediates for making 4-({2-[(aminosulfonyl)amino]ethyl}amino)-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide, which is an inhibitor of indoleamine 2,3-dioxygenase, useful i
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Paragraph 0286
(2015/05/26)
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- MONOBACTAM ORGANIC COMPOUNDS FOR THE TREATMENT OF BACTERIAL INFECTIONS
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This invention pertains generally to antibacterial compounds of Formula I, as further described herein, and pharmaceutically acceptable salts and formulations thereof. In certain aspects, the invention pertains to methods of using such compounds to treat infections such as those caused by Gram-negative bacteria.
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Paragraph 0725; 0726
(2015/11/10)
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- Convenient Synthesis of Novel N -Acylsulfonamides Containing Phosphonate Moiety
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The present study describes a convenient method for the synthesis of new N-acylsulfonamides containing phosphonate moiety. The N-acylsulfonamides were prepared starting from chlorosulfonyl isocyanate (CSI) in four steps (carbamoylation, sulfamoylation, deprotection, and acylation). Trimethylphosphite has been used to introduce the phosphonate moiety into N-acylsulfonamides via Arbuzov reaction. GRAPHICAL ABSTRACT
- Boufas, Wahida,Cheloufi, Hadjer,Bouchareb, Fouzia,Berredjem, Malika,Aouf, Nour-Eddine
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p. 103 - 111
(2015/10/29)
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- FLAP MODULATORS
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The present invention relates to compounds of Formula (I), or a form thereof, wherein ring A, R1, R2, R3, R3′, L, W, and V are as defined herein, useful as FLAP modulators. The invention also relates to pharmaceutical compositions comprising compounds of Formula (I). Methods of making and using the compounds of Formula (I) are also within the scope of the invention
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Paragraph 0673
(2015/11/03)
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- CARBONITRILE DERIVATIVES AS SELECTIVE ANDROGEN RECEPTOR MODULATORS
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The present invention relates to a compound of Formula 1, 2 or 3: I II III wherein A is N or -CR0--, where R0 is hydrogen, C1-C6 linear or branched chain alkyl, etc., Z is -CRe --, or, -N--, where Re is hydrogen, C1 -C6 linear or branched chain alkyl, etc.; R1 is hydrogen, C1 -C6 linear or branched chain alkyl, etc.; R2 are independently hydrogen or C1-C6 linear or branched chain alkyl; R3 and R4 are independently hydrogen, C1C6 linear or branched chain alkyl, etc.;. R5 and R6 are independently hydrogen or C1-C6 linear or branched chain alkyl, etc.; R8 is hydrogen, C1 -C6 linear or branched chain alkyl, etc.; R9 and R10 are independently hydrogen or C1- C6 linear or branched chain alkyl, etc.; Q is --CO--, --(CH2)q--, --(CHRs)q--, or -(CRsRt)q- -, where Rs and Rt are independently C1-C6 linear or branched chain alkyl, aryl, alkylaryl, heteroaryl or alkylheteroaryl; where q is 0, 1, 2, or 3; and, where n is 0, 1, 2, 3, 4 or 5; or, a pharmaceutically acceptable salt thereof, for the treatment of certain diseases, particularly those affected or mediated by the androgen receptor; to compbinations comprising such compounds with a second pharmaceutically active ingredient; to compositions containing such combinations; and to such combinations for the treatment of various diseases, particularly, those affected or mediated by the androgen receptor.
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Page/Page column 134
(2015/12/17)
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- NOVEL 3-INDOL SUBSTITUTED DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND METHODS FOR USE
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The present invention relates to compound of Formula (I) or pharmaceutically acceptable enantiomers, salts or solvates thereof. The invention further relates to the use of the compounds of Formula I as TDO2 inhibitors. The invention also relates to the use of the compounds of Formula I for the treatment and/or HIV, depression, and obesity. The invention also relates to a process for manufacturing compounds of Formula (I).
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Page/Page column 160
(2016/01/12)
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- CRYSTALLINE FORM OF 6-[(4R)-4-METHYL-1,2-DIOXIDO-1,2,6-THIADIAZINAN-2-YL]ISOQUINOLINE-1-CARBONITRILE
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This invention relates to a novel crystalline form of 6-[(4R)-4-methyl-1, 1-dioxido- 1,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile which is useful as a selective androgen receptor modulator (SARM), and to compositions thereof and suitable processes for the preparation thereof.
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Page/Page column 31
(2016/01/29)
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- RECEPTOR ANTAGONISTS
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N-(4-carbamimidoylphenyl)-amide derivatives having utility in therapy as PAR2 receptor antagonists.
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Page/Page column 32
(2014/02/16)
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- SYNERGISTIC COMBINATION OF IMMUNOLOGIC INHIBITORS FOR THE TREATMENT OF CANCER
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In some embodiments, the methods involve the use of a combination of at least two of the following: an inhibitor of indoleamine-2,3-dioxygenase (IDO), an inhibitor of the PD-L1/PD-1 pathway, an inhibitor of CTLA-4, an inhibitor of CD25, or IL-7. The inven
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Paragraph 00196-00197; 00307
(2014/05/24)
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- An efficient method for the synthesis of novel n-acylsulfonamides using tin (IV) chloride as catalysts
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A series of novel N-acylsulfonamides derivatives were synthesized via direct condensation of parent sulfonamide with ethyl lactate as an acylating agent in the presence of tin (IV) chloride (SnCl4) as a Lewis acid catalyst. The sulfonamides were prepared, starting from chlorosulfonyl isocyanate (CSI), in three steps (carbamoylation, sulfamoylation, and deprotection) with excellent yields. Copyright
- Bouchareb, Fouzia,Boufas, Wahida,Cheloufi, Hadjer,Berredjem, Malika,Aouf, Nour-Eddine
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p. 587 - 595
(2014/06/09)
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- Synthesis and antibacterial activity of sulfonamides. SAR and DFT studies
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A series of substituted sulfonamide derivatives were synthesized from chlorosulfonyl isocyanate (CSI) in tree steps (carbamoylation, sulfamoylation and deprotection). Antibacterial activity in vitro of some newly formed compounds investigated against clinical strains Gram-positive and Gram-negative: Escherichia coli and Staphylococcus aureus applying the method of dilution and minimal inhibition concentration (MIC) methods. These compounds have significant bacteriostatic activity with totalities of bacterial strains used. DFT calculations with B3LYP/6-31G(d) level have been used to analyze the electronic and geometric characteristics deduced for the stable structure of three compounds presenting conjugation between a nitrogen atom N through its lone pair and an aromatic ring next to it. The principal quantum chemical descriptors have been correlated with the antibacterial activity.
- Boufas, Wahida,Dupont, Nathalie,Berredjem, Malika,Berrezag, Kamel,Becheker, Imène,Berredjem, Hajira,Aouf, Nour-Eddine
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p. 180 - 185
(2014/07/08)
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- NOVEL 6-BRIDGED HETEROARYLDIHYDROPYRIMIDINES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION
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The invention provides novel compounds having the general formula: wherein R1, R2, R3 and R4 are as defined in the description and in the claims, as well as or pharmaceutically acceptable salts, or tautomerism isomers, or enantiomers, or diastereomers thereof. The invention also contains compositions including the compounds and methods of using the compounds.
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Paragraph 0936
(2014/12/09)
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- 6-BRIDGED HETEROARYLDIHYDROPYRIMIDINES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION
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The invention provides novel compounds having the general formula: wherein R1, R2, R3 and R4 are as defined in the description and in the claims, as well as or pharmaceutically acceptable salts, or tautomerism isomers, or enantiomers, or diastereomers thereof. The invention also contains compositions including the compounds and methods of using the compounds for the treatment or prophylaxis of hepatitis B virus infection.
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Page/Page column 123
(2014/12/12)
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- Ferrier sulfamidoglycosylation of glycals catalyzed by nitrosonium tetrafluoroborate: Towards new carbonic anhydrase glycoinhibitors
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Ferrier sulfamidoglycosylation of glycals catalyzed by nitrosonium tetrafluoroborate allowed the preparation of hydroxysulfamide glycosides in good yields with a good α stereoselectivity. A variety of mono-saccharide derivatives was synthesized using this
- Ombouma, Joanna,Vullo, Daniela,Supuran, Claudiu T.,Winum, Jean-Yves
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p. 6353 - 6359
(2015/02/02)
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- Hypervalent iodine reagent mediated diamination of [60]fullerene with sulfamides or phosphoryl diamides
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A hypervalent iodine-promoted intermolecular diamination reactions of C60 with sulfamides or phosphoryl diamides affords two classes of novel C60-fused cyclic sulfamide or phosphoryl diamide derivatives. The reaction between C60 and sulfamides can be effectively controlled to selectively synthesize diamination products or azafulleroids under PhIO/I2 or PhI(OAc)2/I2 conditions, respectively. Moreover, phosphoryl diamides were first used as an amine source in the diamination of alkenes.
- Yang, Hai-Tao,Lu, Xin-Wei,Xing, Meng-Lei,Sun, Xiao-Qiang,Miao, Chun-Bao
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supporting information
p. 5882 - 5885
(2015/02/19)
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- Synthesis of chromone, quinolone, and benzoxazinone sulfonamide nucleosides as conformationally constrained inhibitors of adenylating enzymes required for siderophore biosynthesis
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MbtA catalyzes the first committed step of mycobactin biosynthesis in Mycobacterium tuberculosis (Mtb) and is responsible for the incorporation of salicylic acid into the mycobactin siderophores. 5′-O-[N-(Salicyl) sulfamoyl]adenosine (Sal-AMS) is an extremely potent nucleoside inhibitor of MbtA that possesses excellent activity against whole-cell Mtb but suffers from poor bioavailability. In an effort to improve the bioavailability, we have designed four conformationally constrained analogues of Sal-AMS that remove two rotatable bonds and the ionized sulfamate group on the basis of computational and structural studies. Herein we describe the synthesis, biochemical, and microbiological evaluation of chromone-, quinolone-, and benzoxazinone-3- sulfonamide derivatives of Sal-AMS. We developed new chemistry to assemble these three heterocycles from common β-ketosulfonamide intermediates. The synthesis of the chromone- and quinolone-3-sulfonamide intermediates features formylation of a β-ketosulfonamide employing dimethylformamide dimethyl acetal to afford an enaminone that can react intramolecularly with a phenol or intermolecularly with a primary amine via addition-elimination reaction(s). The benzoxazinone-3-sulfonamide was prepared by nitrosation of a β-ketosulfonamide followed by intramolecular nucleophilic aromatic substitution. Mitsunobu coupling of these bicyclic sulfonamides with a protected adenosine derivative followed by global deprotection provides a concise synthesis of the respective inhibitors.
- Engelhart, Curtis A.,Aldrich, Courtney C.
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p. 7470 - 7481
(2013/09/02)
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- Amine Substituted Methanesulfonamide Derivatives as Vanilloid Receptor Ligands
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The invention relates to amine substituted methanesulfonamide derivatives as vanilloid receptor ligands, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.
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Paragraph 0650
(2013/04/10)
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- N-(Alkylsulfamoyl)aldimines: Easily deprotected precursors for diarylmethylamine synthesis
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The sequential reaction of chlorosulfonyl isocyanate with t-BuOH, t-BuNH2 and TFA allows formation of H2NSO 2NHBut. Condensation of the latter with Ar1CHO in the presence of Ti(OEt)4 provides the activated imines Ar 1CHNSO2NHBut (59-89%). Commercially available boronic acids add to these imines with good stereoselectivity (76-98% ee) using readily available diene ligands. Simple deprotection with 5% w/w water in pyridine affords free Ar1CHNH2Ar2.
- Crampton, Rosemary H.,Fox, Martin,Woodward, Simon
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p. 599 - 605
(2013/06/27)
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- ISOQUINOLINE AND NAPHTHYRIDINE DERIVATIVES
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The invention provides novel compounds having the general formula(I) wherein A, R1 and R2 are as described herein, compositions including the compounds and use of the compounds for inhibiting angiogenesis by inhibition of MAP4K4.
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Page/Page column 98
(2013/08/15)
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- CYCLIC AMIDE DERIVATIVE
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[Problem] To provide a GPR40 activating agent having, as an active ingredient, a novel compound having a GPR40 agonist action, a salt of the compound, a solvate of the salt or the compound, or the like, particularly, an insulin secretagogues and a prophylactic and/or therapeutic agent against diabetes, obesity, or other diseases. [Means of solving the problem] A compound of Formula (1): (where n is 0 to 2; p is 0 to 4; h is 0 to 3; j is 0 to 3; k is 0 to 2; a ring B is an aryl group or a heteroaryl group; X is O, S, or —NR7—; J1 is —CR11aR11b— or —NR11c—; J2 is —CR12aR12b— or —NR12c—; and R1 to R12c are specific groups), a salt of the compound, or a solvate of the salt or the compound.
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Paragraph 1232
(2013/08/15)
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- Practical asymmetric synthesis of a chiral piperazinone derivative
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A practical asymmetric route to a chiral piperazinone derivative, a fragment of MK-3207, is reported. The amine-bearing benzylic stereocenter is introduced via an asymmetric Pd-catalyzed hydrogenation of a cyclic sulfimidate in the presence of a chiral phosphine ligand. An efficient synthesis of the hydrogenation substrate is described, together with process development of the hydrogenation step and elaboration of the resulting cyclic sulfamate product to the desired piperazinone.
- McLaughlin, Mark,Belyk, Kevin,Chen, Cheng-Yi,Linghu, Xin,Pan, Jun,Qian, Gang,Reamer, Robert A.,Xu, Yingju
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p. 1052 - 1060
(2013/09/12)
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- N-(tert -butoxycarbonyl)- N -[(triethylenediammonium)sulfonyl]azanide: A convenient sulfamoylation reagent for alcohols
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A convenient and efficient procedure is described for the sulfamoylation of alcohols using N-(tert-butoxycarbonyl)-N-[(triethylenediammonium)sulfonyl] azanide (1). The ambient temperature stable reagent 1 reacts with phenols as well as primary and secondary alcohols to give high to modest yields. The relative reaction rate of substrates was determined (primary > phenol > secondary ? tertiary). The reagent's utility as a selective sulfamoylation reagent with polyols is also demonstrated.
- Armitage, Ian,Berne, Alexander M.,Elliott, Eric L.,Fu, Mingkun,Hicks, Frederick,McCubbin, Quentin,Zhu, Lei
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supporting information; experimental part
p. 2626 - 2629
(2012/07/28)
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- NOVEL SULFAMIDE PIPERAZINE DERIVATIVES AS PROTEIN TYROSINE KINASE INHIBITORS AND PHARMACEUTICAL USE THEREOF
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The invention relates to compounds of general Formula (I), Wherein R1, R2, R3, R4, R5, m, n are defined herein, and pharmaceutically acceptable salts, prodrugs, hydrates, or solvates thereof, for use - alone or in combination with one or more other pharmaceutically active compounds- in therapy, as JAK kinase and protein tyrosine kinase inhibitors for preventing, treating or ameliorating diseases and complications thereof, including, for example, psoriasis, atopic dermatitis, rosacea, lupus, multiple sclerosis, rheumatoid arthritis, Type I diabetes, asthma, cancer, autoimmune thyroid disorders, ulcerative colitis, Crohn's disesase, Alzheimer's disease, leukaemia, eye diseases such as diabetic retinopathy and macular degeneration as well as other autoimmune diseases and indications where immunosuppression would be desirable for example in organ transplantation.
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Page/Page column 87-88
(2012/07/27)
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- The discovery of N -[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy] ethoxy]-4-pyrimidinyl]- N ′-propylsulfamide (macitentan), an orally active, potent dual endothelin receptor antagonist
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Starting from the structure of bosentan (1), we embarked on a medicinal chemistry program aiming at the identification of novel potent dual endothelin receptor antagonists with high oral efficacy. This led to the discovery of a novel series of alkyl sulfamide substituted pyrimidines. Among these, compound 17 (macitentan, ACT-064992) emerged as particularly interesting as it is a potent inhibitor of ETA with significant affinity for the ET B receptor and shows excellent pharmacokinetic properties and high in vivo efficacy in hypertensive Dahl salt-sensitive rats. Compound 17 successfully completed a long-term phase III clinical trial for pulmonary arterial hypertension.
- Bolli, Martin H.,Boss, Christoph,Binkert, Christoph,Buchmann, Stephan,Bur, Daniel,Hess, Patrick,Iglarz, Marc,Meyer, Solange,Rein, Josiane,Rey, Markus,Treiber, Alexander,Clozel, Martine,Fischli, Walter,Weller, Thomas
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p. 7849 - 7861
(2012/10/29)
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- PROCESS FOR MAKING CGRP RECEPTOR ANTAGONIST
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The invention encompasses a novel process for making 2-[(8R)-8-(3,5-Difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acetamide, which is a CGRP receptor antagonist useful for the treatment of migraine, using an asymmetric phase-transfer catalysis route. The invention also encompasses an efficient and practical synthesis of the (R)-acid intermediate, and generates the benzylic stereocenter in an enantioselective manner.
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Page/Page column 77-78
(2011/02/24)
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- FLAVIN DERIVATIVES
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The present invention relates novel flavin derivatives and other flavin derivatives, their use and compositions for use as riboswitch ligands and/or anti-infectives. The invention also provides method of making novel flavin derivatives.
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Page/Page column 259-260
(2011/02/24)
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