- A novel regio- and stereoselective synthesis of sulfamidates from 1,2-diols using Burgess and related reagents: A facile entry into β-amino alcohols
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An increasingly targeted functional motif in organic synthesis is the ubiquitous chiral β-amino alcohol. A novel two-step approach for the regio- and stereo-selective synthesis of a wide variety of 1,2-amino alcohols 4 involves the initial construction of chiral sulfamidates 3 from enantiopure diols 1, mediated by Burgess reagent (2, R = Me), followed by mild treatment with aqueous acid. Furthermore, the development of several new Burgess-type reagents 2 (R = CH2Ph, CH2-o-NO2Ph, CH2CHCH2, CH2CCl3) greatly extends the applications of this protocol.
- Nicolaou,Huang, Xianhai,Snyder, Scott A.,Bheema Rao, Paraselli,Bella, Marco,Reddy, Mali V.
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Read Online
- Preparation method of edoxaban
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The invention relates to a new preparation route and a new method for a p-toluenesulfonic acid edoxaban hydrate and intermediates thereof. The new method comprises the steps that a high-reactivity compound 109A4x is prepared; a compound 109C6x is prepared by using a new synthesizing method; new compounds 109E8-01, 109E9x and 109T7-01 are prepared; the p-toluenesulfonic acid edoxaban hydrate is prepared by using the intermediates. By using the new method and the new route, the reaction step of copious cooling is omitted, and dangerous elemental sulfur, high-risk n-butyllithium and high-risk azides are prevented from being used. In a word, by means of the method, the p-toluenesulfonic acid edoxaban hydrate and the key intermediates thereof are more easily and safely prepared at a lower coston an industrialization scale.
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Paragraph 0121-0123
(2019/07/08)
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- N-SULFONYLATED PYRAZOLO[3,4-B]PYRIDIN-6-CARBOXAMIDES AND METHOD OF USE
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The present invention provides for compounds of formula (I) wherein R1, R2, R3, R4, R5, and R6 have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions mediated and modulated by CFTR, including cystic fibrosis, Sj?gren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, and chronic obstructive airway disease. Also provided are pharmaceutical compositions comprised of one or more compounds of formula (I).
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Paragraph 00713-00714; 00719-00720
(2017/04/23)
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- Packaging comprising forms of sodium salt of 4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide
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The invention relates to a packaging comprising a multitude (A) of at least 2 administration units comprising polymorphic trihydrated forms of sodium salt of 4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide; or (B) of at least 2 administration units comprising polymorphic solvated or desolvated forms of sodium salt of 4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide.
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Paragraph 0051
(2016/08/29)
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- Carbonic Anhydrase Glycoinhibitors belonging to the Aminoxysulfonamide Series
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Abstract A general approach for the synthesis of carbonic anhydrases glycoinhibitors belonging to an aminoxysulfonamide series is presented using a Ferrier sulfonamidoglycosylation reaction on glycals. All the compounds showed good in vitro inhibitory activity against four human carbonic anhydrase isoforms, with selectivity against the cytosolic (hCA II) vs the tumor associated (hCA IX and XII) enzymes.
- Ombouma, Joanna,Vullo, Daniella,Dumy, Pascal,Supuran, Claudiu T.,Winum, Jean-Yves
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supporting information
p. 819 - 821
(2015/08/11)
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- Carbonic anhydrase inhibitory properties of novel benzylsulfamides using molecular modeling and experimental studies
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In this study, a series of sulfamoyl carbamates and sulfamide derivatives were synthesized. Six commercially available benzyl amines and BnOH were reacted with chlorosulfonyl isocyanate (CSI) to give sulfamoyl carbamates. Pd-C catalyzed hydrogenolysis reactions of carbamates afforded sulfamides. The inhibition effects of novel benzylsulfamides on the carbonic anhydrase I, and II isoenzymes (CA I, and CA II) purified from fresh human blood red cells were determined by Sepharose-4B-L-Tyrosine-sulfanilamide affinity chromatography. In vitro studies were shown that all of novel synthesized benzylsulfamide analogs inhibited, concentration dependently, both hCA isoenzyme activities. The novel benzylsulfamide compounds investigated here exhibited nanomolar inhibition constants against the two isoenzymes. Ki values were in the range of 28.48 ± 0.01-837.09 ± 0.19 nM and 112.01 ± 0.01-268.01 ± 0.22 nM for hCAI and hCA II isoenzymes, respectively. Molecular modeling approaches were also applied for studied compounds.
- G?ksu, Süleyman,Naderi, Ali,Akbaba, Yusuf,Kalin, Pinar,Akinciolu, Akin,Gülin, Ilhami,Durdagi, Serdar,Salmas, Ramin Ekhteiari
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- N- (6- ( (2R,3S) -3,4-DIHYDROXYBUTAN-2-YLOXY) -2- (4 - FLUOROBENZYLTHIO) PYRIMIDIN- 4 - YL) -3- METHYLAZETIDINE- 1 - SULFONAMIDE AS CHEMOKINE RECEPTOR MODULATOR
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There is provided a compound which is (a) a pyrimidine sulfonamide of formula (I) or (b) a pharmaceutically acceptable salt thereof, crystalline forms of the compound, processes for obtaining the compound, pharmaceutical intermediates used in the manufacture of the compound, and pharmaceutical compositions containing the compound. The compound is useful in the treatment of a disease/condition in which modulation of chemokine receptor activity is beneficial.
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Page/Page column 47; 48
(2013/03/26)
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- BRANCHED OXATHIAZINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, USE THEREOF AS MEDICINE AND DRUG CONTAINING SAID DERIVATIVES AND USE THEREOF
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The invention relates to compounds of formula (I) and to the physiologically compatible salts thereof. Said compounds are suitable, for example, for treating hyperglycemia.
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Paragraph 0414-0418
(2014/02/15)
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- Structure-activity relationships and key structural feature of pyridyloxybenzene-acylsulfonamides as new, potent, and selective peroxisome proliferator-activated receptor (PPAR) γ Agonists
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In our search for a novel class of non-TZD, non-carboxylic acid peroxisome proliferator-activated receptor (PPAR) γ agonists, we explored alternative lipophilic templates to replace benzylpyrazole core of the previously reported agonist 1. Introduction of a pentylsulfonamide group into arylpropionic acids derived from previous in-house PPARγ ligands succeeded in the identification of 2-pyridyloxybenzene-acylsulfonamide 2 as a lead compound. Docking studies of compound 2 suggested that a substituent para to the central benzene ring should be incorporated to effectively fill the Y-shaped cavity of the PPARγ ligand-binding domain (LBD). This strategy led to significant improvement of PPARγ activity. Further optimization to balance in vitro activity and metabolic stability allowed the discovery of the potent, selective and orally efficacious PPARγ agonist 8f. Structure-activity relationship study as well as detailed analysis of the binding mode of 8f to the PPARγ-LBD revealed the essential structural features of this series of ligands.
- Rikimaru, Kentaro,Wakabayashi, Takeshi,Abe, Hidenori,Tawaraishi, Taisuke,Imoto, Hiroshi,Yonemori, Jinichi,Hirose, Hideki,Murase, Katsuhito,Matsuo, Takanori,Matsumoto, Mitsuharu,Nomura, Chisako,Tsuge, Hiroko,Arimura, Naoto,Kawakami, Kazutoshi,Sakamoto, Junichi,Funami, Miyuki,Mol, Clifford D.,Snell, Gyorgy P.,Bragstad, Kenneth A.,Sang, Bi-Ching,Dougan, Douglas R.,Tanaka, Toshimasa,Katayama, Nozomi,Horiguchi, Yoshiaki,Momose, Yu
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experimental part
p. 3332 - 3358
(2012/07/14)
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- Process development and large-scale synthesis of a c-Met kinase inhibitor
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A highly convergent synthesis of c-Met kinase inhibitor 1 has been demonstrated on a multikilogram scale using three key fragments: dihalotricyclic core 2, chiral sulfamide side chain 3, and pyrazole boronic ester 4. The chirality in sulfamide side chain 3 was installed using the cheap and readily available starting material (S)-epichlorohydrin. A total of 2.71 kg of 1 were isolated in seven steps (the longest linear sequence).
- Stewart, Gavin W.,Brands, Karel M. J.,Brewer, Sarah E.,Cowden, Cameron J.,Davies, Antony J.,Edwards, John S.,Gibson, Andrew W.,Hamilton, Simon E.,Katz, Jason D.,Keen, Stephen P.,Mullens, Peter R.,Scott, Jeremy P.,Wallace, Debra J.,Wise, Christopher S.
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experimental part
p. 849 - 858
(2011/03/20)
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- A critical electrostatic interaction mediates inhibitor recognition by human asparagine synthetase
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The first sulfoximine-based inhibitor of human asparagine synthetase (ASNS) with nanomolar potency has been shown to suppress proliferation of asparaginase-resistant MOLT-4 cells in the presence of l-asparaginase. This validates literature hypotheses concerning the viability of human ASNS as a target for new drugs against acute lymphoblastic leukemia and ovarian cancer. Developing structure-function relationships for this class of human ASNS inhibitors has proven difficult, however, primarily because of the absence of rapid synthetic procedures for constructing highly functionalized sulfoximines. We now report conditions for the efficient preparation of these compounds by coupling sulfoxides and sulfamides in the presence of a rhodium catalyst. Access to this methodology has permitted the construction of two new adenylated sulfoximines, which were expected to exhibit similar binding affinity and better bioavailability than the original human ASNS inhibitor. Steady-state kinetic characterization of these compounds, however, has revealed the importance of a localized negative charge on the inhibitor that mimics that of the phosphate group in a key acyl-adenylate reaction intermediate. These experiments place an important constraint on the design of sulfoximine libraries for screening experiments to obtain ASNS inhibitors with increased potency and bioavailability.
- Ikeuchi, Hideyuki,Meyer, Megan E.,Ding, Yun,Hiratake, Jun,Richards, Nigel G.J.
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experimental part
p. 6641 - 6650
(2009/12/09)
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- A novel, easy and mild preparation of sulfilimines from sulfoxides using the Burgess reagent
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A novel preparation of sulfilimines from the corresponding sulfoxides using the Burgess reagent is described. The reaction is general to dialkyl- and aryl alkyl sulfoxides and proceeds under mild conditions in benzene. A variety of protecting groups can be introduced on the nitrogen of the sulfilimine by choosing the appropriate Burgess reagent.
- Raghavan, Sadagopan,Mustafa, Shaik,Rathore, Kailash
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p. 4256 - 4259
(2008/09/21)
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- PYRIDAZINONE COMPOUNDS
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The invention is directed to pyridazinone compounds and pharmaceutical compositions containing such compounds that are useful in treating infections by hepatitis C virus.
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Page/Page column 133-134
(2008/12/07)
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- HETEROCYCLIC CYCLOPAMINE ANALOGS AND METHODS OF USE THEREOF
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The present invention relates to steroidal alkaloid-like compounds that can be used in the treatment of hedgehog pathway related disorders, particularly cancer.
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Page/Page column 47
(2008/12/08)
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- Phenylglycinamide and pyridylglycinamide derivatives useful as anticoagulants
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The present invention provides novel phenylglycinamide derivatives of Formula (I) or (IV): or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the variables W, W1, Y, Z, R7, R8, R9, and R11 are as defined herein. These compounds are selective inhibitors of factor VIIa which can be used as medicaments.
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Page/Page column 53
(2010/11/25)
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- Inhibitors of HCV NS5B polymerase: Synthesis and structure-activity relationships of N-alkyl-4-hydroxyquinolon-3-yl-benzothiadiazine sulfamides
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Substituted N-alkyl-4-hydroxyquinolon-3-yl-benzothiadiazine sulfamides were investigated as inhibitors of genotype 1 HCV polymerase. Structure-activity relationship patterns for this class of compounds are discussed.
- Chris Krueger,Madigan, Darold L.,Jiang, Wen W.,Kati, Warren M.,Liu, Dachun,Liu, Yaya,Maring, Clarence J.,Masse, Sherie,McDaniel, Keith F.,Middleton, Tim,Mo, Hongmei,Molla, Akhteruzzaman,Montgomery, Debra,Pratt, John K.,Rockway, Todd W.,Zhang, Rong,Kempf, Dale J.
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p. 3367 - 3370
(2007/10/03)
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- Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions
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The present invention relates to the CGRP antagonists of general formula wherein A, X, Q and R1 to R3 are defined as in claim 1, the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates, mixtures and salts thereof and the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids, pharmaceutical compositions containing these compounds, their use and processes for preparing them.
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Page/Page column 158
(2008/06/13)
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- Deoxyribosyl analogues of methionyl and isoleucyl sulfamate adenylates as inhibitors of methionyl-tRNA and isoleucyl-tRNA synthetases
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2′-Deoxy, 3′-deoxy, and 2′,3′-dideoxyribosyl surrogates of isoleucyl and methionyl sulfamate adenylates have been investigated to identify the pharmacophoric importance of the ribose group for the inhibition of Escherichia coli methionyl-tRNA (MRS) and isoleucyl-tRNA (IRS) synthetases. Molecular modeling of 2′,3′-dideoxyribosyl Met-NHSO2-AMP (9) with the crystal structure of E. coli MRS revealed that the lack of the two hydroxyl groups on ribose was compensated by the formation of an extra hydrogen bond between the ring oxygen and His24, resulting in a small activity reduction.
- Sung, Eun Kim,Su, Yeon Kim,Kim, Sunghoon,Kang, Taehee,Lee, Jeewoo
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p. 3389 - 3393
(2007/10/03)
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- NOVEL KETOAMIDES WITH CYCLIC P4'S AS INHIBITORS OF NS3 SERINE PROTEASE OF HEPATITIS C VIRUS
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The present invention discloses novel compounds which have HCV protease inhibitory activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such compounds as well as methods of using them to treat disorders associated with the HCV protease.
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Page/Page column 94-95
(2008/06/13)
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- SELECTED CGRP ANTAGONISTS, METHODS FOR THE PRODUCTION THEREOF, AND USE THEREOF AS MEDICAMENTS
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The invention relates to CGRP antagonists of general formula (I), wherein A, X, Q, and R1 to R3 are defined as indicated in claim 1, the tautomers, isomers, diastereomers, enantiomers, hydrates, mixtures, and salts thereof, and the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids, medicaments containing said compounds, the use thereof, and methods for the production thereof.
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Page/Page column 15
(2008/06/13)
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- Sulfamide derivatives as transition state analogue inhibitors for carboxypeptidase A
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3-Phenyl-2-sulfamoyloxypropionic acid (2), 2-benzyl-3-sulfamoylpropionic acid (3), and N-(N-hydroxysulfamoyl)phenylalanine (5) have been synthesized and evaluated as inhibitors for carboxypeptidase A (CPA) to find that they inhibit the enzyme competitively with the Ki values in the μM range, suggesting that their binding modes to CPA are analogous to each other, and resemble the binding mode of N-sulfamoylphenylalanine (1) that has been established by the X-ray crystallographic method to form a complex with CPA in a manner reminiscent of the binding of a transition state in the catalytic pathway. It was concluded thus that they are a new type of transition state analogue inhibitors for CPA. (R)-N-Hydroxy-N-sulfamoyl-β-phenylalanine (8) was shown to be also a potent CPA inhibitor (Ki=39μM), the high potency of which may be ascribed to the involvement of the hydroxyl in the binding of CPA, most likely forming bidentate coordinative bonds to the zinc ion in CPA together with the sulfamoyl oxygen atom.
- Park, Jung Dae,Kim, Dong H.
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p. 2349 - 2356
(2007/10/03)
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- New uses for the Burgess reagent in chemical synthesis: Methods for the facile and stereoselective formation of sulfamidates, glycosylamines, and sulfamides
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Although the Burgess reagent (methoxycarbonylsulfamoyltriethylammonium hydroxide, inner salt) has found significant use in chemical synthesis as a dehydrating agent, almost no work has been directed towards its potential in other synthetic applications. As this article will detail, we have found that the Burgess reagent is remarkably effective at accomplishing a number of non-dehydrative synthetic tasks when applied to appropriate substrates, such as the formation of sulfamidates from 1,2-diols or epoxyalcohols, α- and β-glycosylamines from carbohydrates, and cyclic sulfamides from 1,2-aminoalcohols. Beyond delineating the power of these new reaction manifolds, we also describe the construction of a group of alternative Burgess-type reagents that extends the scope of these new reactions even further.
- Nicolaou,Snyder, Scott A.,Longbottom, Deborah A.,Nalbandian, Annie Z.,Huang, Xianhai
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p. 5581 - 5606
(2007/10/03)
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- NOVEL SUBSTITUTED SULFAMATE ANTICONVULSANT DERIVATIVES
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The present invention is directed to novel compounds of the formula (I) wherein X, R1, R2 , R3, R4, R5 and R6 are as described in the specification, processes for the preparation of and pharmaceutical compositions comprising said derivatives. The compounds of the present invention are useful for the treatment of epilepsy.The invention is further directed to a process for the preparation of compounds of formula (XX), wherein X, R3, R4, R5 and R6 are as described in the specification.
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Page/Page column 87; 88
(2008/06/13)
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- Sulfamide-based inhibitors for carboxypeptidase A. Novel type transition state analogue inhibitors for zinc proteases
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N-Sulfamoylphenylalanine and its derivatives having varied alkyl groups on the terminal amino group were designed rationally as transition state analogue inhibitors for carboxypeptidase A (CPA) and synthesized. In CPA inhibitory assays the parent compound having the (S)-configuration, i.e., (S)-1a, showed potent inhibitory activity with the Ki value of 0.64 μM. Its enantiomer was shown to be much less potent (Ki = 470 μM). Introduction of an alkyl group such as methyl or isopropyl group on the terminal amino group of (S)-1a lowered the inhibitory potency drastically. Introduction of a methyl group on the internal amino group of (S)-1a also caused a drastic reduction of the inhibitory activity. The structure of the CPA-(S)-1a complex determined by single-crystal X-ray diffraction reveals that the sulfamoyl moiety interacts with the zinc ion and functional groups at the active site of CPA, which is reminiscent of the postulated stabilization mode of a tetrahedral transition state in the CPA-catalyzed hydrolysis of a peptide substrate. On the basis of the design rationale and the binding mode of (S)-1a to CPA shown by X-ray crystallographic analysis, the present inhibitors are inferred to be a novel type of transition state analogue inhibitor for CPA.
- Park, Jung Dae,Kim, Dong H.,Kim, Seung-Jun,Woo, Joo-Rang,Ryu, Seong Eon
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p. 5295 - 5302
(2007/10/03)
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- Synthesis of a N-acylsulfamide linked dinucleoside and its incorporation into an oligonucleotide
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A N-acylsulfamide linked thymidine dinucleoside was synthesized and incorporated into an oligonucleotide (ON). The interest is in a linkage analog that has a higher pKa relative to a phosphodiester and when incorporated into ONs is capable of helix formation with complementary RNA. The hybridization property of the resultant ON with RNA was shown to result in significant destabilization.
- Zhang, Jiancun,Matteucci, Mark D.
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p. 2213 - 2216
(2007/10/03)
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- Sulfamates as antiglaucoma agents
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Sulfamate esters of the formula where A is aryloxyalkyl, p is the number of unreacted hydroxy groups present on the alkyl moiety and may be zero, z is the number of --OS(O)2 NR1 R2 groups attached to carbons of the alkyl moiety and is always at least one; R1 and R2 are selected from hydrogen, loweralkyl, carboxy, and the like are useful in treating glaucoma.
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- Compounds having one or more aminosulfaonyloxy radicals useful as pharmaceuticals
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Methods of treating chronic arthritis and osteoporosis which utilize both known and novel compounds which would fall under the general formula:(HO)p--A--[--OS(O) 2 NR 1 R 2 ] zwherein A encompasses a wide range of values including but not limited to aryl, loweralkyl, cycloalkyl, and carbohydrates including sucrose and fructose; p is equal to the number of unreacted hydroxy groups contained on the molecule and may be zero; z is the number of --OS(O) 2 NR 1 R 2 groups and is always at least one; R 1 and R 2 are selected from hydrogen, loweralkyl, carboxy and the like; a novel process for preparing the compounds is provided wherein an appropriate sulfamic acid aryl ester is reacted with a hydroxy substituted A radical which may or may not contain thereon protected carboxyl, amino or hydroxy substituents, in an aprotic solvent containing a tertiary amine base. Pharmaceutical compositions for the treatment of chronic arthritis and osteoporosis are also provided.
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- Synthesis and Physicochemical Properties of Sulfamate Derivatives as Topical Antiglaucoma Agents
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Several imidazolylphenyl sulfamate and (imidazolylphenoxy)alkyl sulfamate derivatives were synthesized and evaluated as topically active carbonic anhydrase inhibitors. Water solubility, pKa, carbonic anhydrase inhibition, and partition coefficient for the compounds were measured. Sulfamic acid 2-ethyl ester monohydrochloride (16) has the best combination of properties and showed excellent topical activity in lowering the intraocular pressure in New Zealand white rabbits.
- Lo, Young S.,Nolan, Joseph C.,Maren, Thomas H.,Welstead, William J.,Gripshover, David F.,Shamblee, Dwight A.
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p. 4790 - 4794
(2007/10/02)
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