- Synthesis of Epibatidine Analogues by Pyrrole Diels–Alder Reactions: Rapid Access to Azabicyclo[2.2.1]heptane and 3,8-Diazabicyclo[3.2.1]octane Scaffolds for Library Synthesis
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Analogues of the nicotinic acetylcholine antagonist epibatidine, suitable for diversification, were synthesized by application of a pyrrole Diels–Alder strategy, allowing rapid generation of azabicyclo[2.2.1]heptane bicyclic cores. Further molecular complexity could be accessed by using intramolecular Diels–Alder reactions, or ring expansion by ozonolysis–reductive amination chemistry. Scaffolds were designed such that they could be orthogonally deprotected, yielding three points of diversity for library synthesis, exemplified by 24 compounds synthesized from four cores.
- Murray, Alexander T.,Packard, Emma,Nortcliffe, Andrew,Lewis, William,Hamza, Daniel,Jones, Geraint,Moody, Christopher J.
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- Silica gel-promoted convenient synthesis of 2-bromo-3-hydroxybenzoate derivatives
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A convenient silica gel-promoted synthesis of 2-bromo-3-hydroxybenzoate derivatives has been developed via the Diels-Alder reaction of furans with methyl 3-bromopropiolate, followed by a ring-opening aromatization. In addition, 2-bromo-3-methoxybenzoate, derived from 2-bromo-3-hydroxybenzoate with iodomethane, was found to be a good substrate for Pd-catalyzed cross-coupling reactions, despite its sterically hindered structure.
- Shinohara, Hiroyuki,Sonoda, Motohiro,Hayagane, Naoya,Kita, Shota,Tanimori, Shinji,Ogawa, Akiya
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- Development of an enolate alkynylation approach towards the synthesis of the taiwanschirin natural products
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Through the use of model studies, an approach was conceived towards the synthesis of the taiwanschirin family of natural products. These are structurally complex compounds which represent highly challenging and biologically active targets for total synthesis. This work describes a successful synthesis of the complex taiwanschirin fused [8,6,5] core through a novel alkynylation reaction coupled with an intramolecular Heck reaction used to construct the 8-membered ring.
- Christensen, Kirsten E.,Donohoe, Timothy J.,Haughey, Maxwell B.,Poole, Darren L.
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p. 13392 - 13397
(2021/11/01)
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- Stable Pyrrole-Linked Bioconjugates through Tetrazine-Triggered Azanorbornadiene Fragmentation
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An azanorbornadiene bromovinyl sulfone reagent for cysteine-selective bioconjugation has been developed. Subsequent reaction with dipyridyl tetrazine leads to bond cleavage and formation of a pyrrole-linked conjugate. The latter involves ligation of the tetrazine to the azanorbornadiene-tagged protein through inverse electron demand Diels–Alder cycloaddition with subsequent double retro-Diels–Alder reactions to form a stable pyrrole linkage. The sequence of site-selective bioconjugation followed by bioorthogonal bond cleavage was efficiently employed for the labelling of three different proteins. This method benefits from easy preparation of these reagents, selectivity for cysteine, and stability after reaction with a commercial tetrazine, which has potential for the routine preparation of protein conjugates for chemical biology studies.
- Bernardes, Gon?alo J. L.,Corzana, Francisco,Gil de Montes, Enrique,Hoyt, Emily A.,Istrate, Alena,Jiménez-Moreno, Ester,Jiménez-Osés, Gonzalo,Moreno-Vargas, Antonio J.,Navo, Claudio D.,Robina, Inmaculada
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supporting information
p. 6196 - 6200
(2020/02/25)
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- Intermolecular cyclotrimerization of haloketoalkynes and internal alkynes: Facile access to arenes and phthalides
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A highly chemo-and regioselective cyclo(co)trimerization between 3-halopropiolamides and symmetrical internal alkynes is reported. The reaction is catalyzed by CpRuCl(COD) and proceeds under air at ambient temperature in ethanol with no additional precautions. Iodo-, bromo-, and chloropropiolamides, esters, and ketones are viable coupling partners and, in a 2?:?1 stoichiometry relative to internal alkyne, yield fully-substituted arenes in a single step. The highest regioselectivities (96% single isomer) were observed when employing 2° and 3°-halopropiolamides. A mechanistic hypothesis accounting for this selectivity is proposed. Notably, by using 1,4-butynediol as the internal alkyne, in situ lactonization following [2+2+2]-cycloaddition generates therapeutically-relevant phthalide pharmacophores directly. This journal is
- Silvestri,Oakdale
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supporting information
p. 13417 - 13420
(2020/11/10)
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- 5-HYDROXY-7-OXABICYCLO[2.2.1]HEPTANE-2-CARBOXAMIDE DERIVATIVES FOR INDUCING CHONDROGENESIS FOR TREATING JOINT DAMAGE
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The present invention provides 5-hydroxy-7- oxabicyclo[2.2.1]heptane-2-carboxamide derivatives of Formula (1) wherein the variables are as defined herein. The present invention further provides pharmaceutical compositions comprising such compounds. The compounds are used for inducing chondrogenesis, in methods of treating or preventing joint damage, resulting from joint injury or arthritis, and for inducing hyaline cartilage production. The present description discloses the preparation of exemplary compounds as well as pharmacological data thereof (examples 1 to 89; tables 1 and 2). An exemplary compound is e.g. rac-(1R,2R,3S,4R,5S)-N-(2-fluoro-5- (trifluoromethyl)phenyl)-5-hydroxy-3-(3-(trifluoromethyl)phenyl)-7- oxabicyclo[2.2.1]heptane-2-carboxamid (example 1).
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(2020/07/05)
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- 6-HYDROXY-8-OXATRICYCLO[3.2.1.02,4]OCTANE-2-CARBOXAMIDE DERIVATIVES FOR INDUCING CHONDROGENESIS FOR TREATING JOINT DAMAGE
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The present invention provides 6-hydroxy-8- oxatricyclo[3.2.1.02,4]octane-2-carboxamide derivatives of Formula (1) wherein the variables are as defined herein. The present invention further provides pharmaceutical compositions comprising such compounds. The compounds are used for inducing chondrogenesis, in methods of treating or preventing joint damage, resulting from joint injury or arthritis, and for inducing hyaline cartilage production. The present description discloses the preparation of exemplary compounds as well as pharmacological data thereof (examples 1 to 82; tables 1 and 2). An exemplary compound is e.g. rac-(1R,2R,4S,5R,6S)-4-(2- fluoropyridin-4-yl)-6-hydroxy-N-(4-(trifluoromethyl)pyridin-2-yl)-8- oxatricyclo[3.2.1.02,4]octane-2-carboxamide (example 1).
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(2020/07/06)
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- CERAMIDE GALACTOSYLTRANSFERASE INHIBITORS FOR THE TREATMENT OF DISEASE
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Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with the enzyme ceramide galactosyltransferase (CGT), such as, for example, lysosomal storage diseases. Examples of lysosomal storage diseases include, for example, Krabbe disease and Metachromatic Leukodystrophy.
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Paragraph 001667; 001668
(2018/07/29)
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- COMPOUNDS AND COMPOSITIONS FOR INDUCING CHONDROGENESIS
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The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; (I) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein the variables are as defined herein. The present invention further provides pharmaceutical compositions comprising such compounds; and methods of using such compounds for treating joint damage or injury in a mammal, for inducing hyaline cartilage production or for inducing differentiation of chondrogenic progenitor cells into mature chondrocytes.
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Page/Page column 36
(2019/01/06)
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- Discovery of aminocyclohexene analogues as selective and orally bioavailable hNav1.7 inhibitors for analgesia
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hNav1.7 receives a lot of attention owing to its attractive mechanism of action in pain processing pathway. We have previously reported our design of a novel series of tetrahydropyridine analogues towards hNav1.7 selective inhibitors. Herein, we disclose further efforts to the optimization of hit compound (?)-6, which led to the identification of aminocyclohexene analogues (?)-9 and (?)-17 with good potency, high selectivity, and minimal CYP inhibition. Both compounds (?)-9 and (?)-17 demonstrated improved pharmacokinetic profiles in rats, and robust efficacy in rat formalin-induced nociception and spinal nerve ligation (SNL) models.
- Teng, Mingxing,Wu, Wentao,Li, Zhixiang,Yang, Guangwen,Qin, Jian,Wang, Yikai,Hu, Zhijing,Dong, Haiheng,Hou, Lijuan,Hu, Guoping,Shen, Liang,Zhang, Yang,Li, Jian,Chen, Shuhui,Tian, Jingwei,Ye, Liang,Zhang, Jianzhao,Wang, Hongbo
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supporting information
p. 4979 - 4984
(2017/10/20)
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- CYCLOALKYL-LINKED DIHETEROCYCLE DERIVATIVES
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The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein A, L, D, R1-R15, w, x, y, and z are defined herein. The novel cycloalkyl-linked diheterocycle derivatives that are useful in the treatment of abnormal cell growth, such as cancer, in mammals. The present invention also relates to pharmaceutical compositions containing the compounds and to methods of using the compounds and compositions in the treatment of abnormal cell growth in mammals.
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Page/Page column 148
(2015/11/24)
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- COMPOUNDS AND COMPOSITIONS FOR INDUCING CHONDROGENESIS
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The present invention provides compounds of formula I: or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein the variables are as defined herein. The present invention further provides pharmaceutical compositions comprising such compounds, and methods of using such compounds for treatment of joint damage or joint injury in a mammal, and for inducing differentiation of mesenchymal stem cells into chondrocytes.
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Paragraph 0372
(2015/12/01)
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- COMPOUNDS AND USES THEREOF FOR THE MODULATION OF HEMOGLOBIN
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Provide herein are compounds and pharmaceutical compositions suitable as modulators of hemoglobin, methods and intermediates for their preparation, and methods for their use in treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygenation.
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Paragraph 0342
(2015/05/26)
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- Cobalt(II)-catalyzed electrophilic alkynylation of 1,3-dicarbonyl compounds to form polysubstituted furans via π-π Activation
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Polysubstituted furans were obtained with excellent yields via the electrophilic alkynylation of 1,3-dicarbonyl compoundsws with phenyl- or ester-substituted brominated alkynes. The reaction is catalyzed by the inexpensive and readily available catalyst, cobalt(II) chloride, and has a wide substrate scope. The C(sp)-C(sp3) coupling occurs under mild conditions with short reaction times and does not require an inert atmosphere or ligands. It is proposed that the reaction proceeds through a chelation complex of cobalt(II) with the deprotonated 1,3-dicarbonyl compound.
- Roslan, Irwan Iskandar,Sun, Jiulong,Chuah, Gaik-Khuan,Jaenicke, Stephan
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supporting information
p. 719 - 726
(2015/03/18)
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- TETRAAZA-CYCLOPENTA[A]INDENYL DERIVATIVES
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The present invention provides compounds of Formula (I) as M1 receptor positive allosteric modulators for the treatment of diseases mediated by the muscarinic M1 mediator.
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Page/Page column 100
(2015/01/09)
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- Tetraaza-cyclopenta[a]indenyl derivatives
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The present invention provides compounds of Formula (I) as M1 receptor positive allosteric modulators for the treatment of diseases mediated by the muscarinic M1 mediator.
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Paragraph 0105
(2015/01/18)
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- Ruthenium-catalyzed cycloadditions of 1-haloalkynes with nitrile oxides and organic azides: Synthesis of 4-haloisoxazoles and 5-halotriazoles
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(Cyclopentadienyl)(cyclooctadiene) ruthenium(II) chloride [CpRuCl(cod)] catalyzes the reaction between nitrile oxides and electronically deficient 1-choro-, 1-bromo-, and 1-iodoalkynes leading to 4-haloisoxazoles. Organic azides are also suitable 1,3-dipoles, resulting in 5-halo-1,2,3-triazoles. These air-tolerant reactions can be performed at room temperature with 1.25 equivalents of the respective 1,3-dipole relative to the alkyne component. Reactive 1-haloalkynes include propiolic amides, esters, ketones, and phosphonates. Post-functionalization of the halogenated azole products can be accomplished by using palladium-catalyzed cross-coupling reactions and by manipulation of reactive amide groups. The lack of catalysis observed with [Cp RuCl(cod)] (Cp=pentamethylcyclopentadienyl) is attributed to steric demands of the Cp* (η5-C5Me5) ligand in comparison to the parent Cp (η5-C5H5). This hypothesis is supported by the poor reactivity of [(η5-C 5Me4CF3)RuCl(cod)], which serves as a an isosteric mimic of Cp* and as an isoelectronic analogue of Cp.
- Oakdale, James S.,Sit, Rakesh K.,Fokin, Valery V.
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supporting information
p. 11101 - 11110,10
(2014/11/07)
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- Copper-catalyzed cross-coupling of vinylsiloxanes with bromoalkynes: Synthesis of enynes
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Enynes are versatile building blocks in organic synthesis. A copper-catalyzed Hiyama-type cross-coupling of vinylsiloxanes with bromoalkynes is presented. This mild and efficient method led to the formation of various sensitive enynes. The use of cis, trans, and 1,1′-disubstituted vinylsiloxanes was allowed, and full retention of stereochemistry was observed. Sensitive groups such as halides, unsaturated ketones, and aldehydes were fully tolerated.
- Cornelissen, Loic,Lefrancq, Maxime,Riant, Olivier
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supporting information
p. 3024 - 3027
(2014/06/23)
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- BICYCLIC HETEROCYCLE DERIVATIVES AND METHODS OF USE THEREOF
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The present invention relates to Bicyclic Heterocycle Derivatives, compositions comprising a Bicyclic Heterocycle Derivative, and methods of using the Bicyclic Heterocycle Derivatives for treating or preventing obesity, diabetes, a metabolic disorder, a cardiovascular disease or a disorder related to the activity of GPR119 in a patient.
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Page/Page column 201
(2009/05/30)
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- Soluble and polymer-supported 2- and 3-benzylated furans for the preparation of α,β-ethylenic carbonyl compounds
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Soluble and polymer-supported 2- and 3-benzylated furans were subjected to a sequence involving a Diels-Alder reaction with α,β-acetylenic carbonyl compounds, a Michael addition, and a subsequent retro-Diels-Alder reaction to yield olefinic compounds. On solid support, this traceless strategy is advantageous since pure compounds were released in the thermal cycloreversion step. The fur-2-ylated resin allowed a highly diastereoselective synthesis.
- Albert, Sébastien,Soret, Adrien,Blanco, Luis,Deloisy, Sandrine
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p. 2888 - 2900
(2007/10/03)
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- Organocatalytic asymmetric direct α-alkynylation of cyclic β-ketoesters
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The first organocatalytic enantioselective direct α-alkynylation of β-ketoesters and 3-acyl oxindoles is described. It is demonstrated that activated β-halo-alkynes undergo nucleophilic acetylenic substitution catalyzed by chiral phase-transfer compounds to afford the alkynylated products in high yields and excellent enantioselectivities. The potential of the reaction is first demonstrated for various alkynylating reagents having chloride and bromide as the leaving groups and substituents such as allyl and alkyl esters, amides, ketones, and sulfones. These reactions proceed with 74-99% yield and 88-97% ee. Then the scope in nucleophile is demonstrated for a large number of cyclic β-ketoesters with various ring-sizes and for oxindoles as well. The corresponding optically active products are formed in high yields and with enantioselectivities up to 98% ee. The procedure allows for the stereocontrolled attachment of an ethynyl unit in the α-position to the carbonyl compound by facile removal of the activating group, and this has been demonstrated for a number of the optically active allyl esters. Furthermore, the synthesis of optically active 1,4-enynes is also shown. The isolation and characterization by X-ray analysis of the catalyst with p-nitrophenolate as the counterion allowed us to propose a model of the catalyst-substrate intermediate which might account for the observed enantioselectivity of the organocatalytic enantioselective α-alkynylation reaction. Furthermore, it is suggested that this intermediate is also the reactive species for a number of other electrophiles adding to β-ketoesters giving enantioselectivities in the range of 90-98% ee.
- Poulsen, Thomas B.,Bernardi, Luca,Aleman, Jose,Overgaard, Jacob,Jorgensen, Karl Anker
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p. 441 - 449
(2007/10/03)
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- QSAR studies and pharmacophore identification for arylsubstituted cycloalkenecarboxylic acid methyl esters with affinity for the human dopamine transporter
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Data from a series of 29 monoamine transport inhibitors were used to generate 2D and 3D QSAR models for their binding affinity to the human dopamine transporter (hDAT). Among the inhibitors were many non-nitrogen containing compounds. The 2D QSAR analysis resulted in the equation -log Ki = 4.00 - 3.93ELUMO - 0.67EHOMO - 3.24σp, which predicted the importance of electron withdrawing groups in the aromatic moiety. However, the model failed to predict the observed poor binding of nitro-substituted compounds. In contrast, a derived 3D QSAR model was capable of predicting these more correctly.
- Christensen, Helena S.,Boye, Soren V.,Thinggaard, Jacob,Sinning, Steffen,Wiborg, Ove,Schiott, Birgit,Bols, Mikael
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p. 5262 - 5274
(2008/03/15)
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- Oligomers of β-amino acid bearing non-planar amides form ordered structures
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In this report, we explore the feasibility of using bicyclic chiral β-amino acids, (1R,2R,4S)- and (1S,2S,4R)-7-azabicyclo[2.2.1]heptane-2-carboxylic acid (R-Ah2c and S-Ah2c, respectively), to prepare novel peptides with unique properties. Facile cis-trans isomerization of the non-planar amide bonds of these β-amino acids should result in great flexibility of the backbone structure of β-peptides containing them. Indeed, oligomers of these amino acids showed thermostability and characteristic CD absorptions, which were not concentration-dependent, suggesting that the oligomers remained monomeric. The results indicated the formation of self-organized monomeric structures with chain-length-dependent stabilization. Energy calculations suggested that the peptides can take helical structures in which the energy barriers to cis-trans isomerization are greater for the central amide bonds than for the terminal amides.
- Otani, Yuko,Futaki, Shiroh,Kiwada, Tatsuto,Sugiura, Yukio,Muranaka, Atsuya,Kobayashi, Nagao,Uchiyama, Masanobu,Yamaguchi, Kentaro,Ohwada, Tomohiko
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p. 11635 - 11644
(2007/10/03)
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- COMPOUNDS HAVING BOTH α7 NICOTINIC AGONIST ACTIVITY AND 5HT3 ANTAGONIST ACTIVITY FOR TREATMENT OF CNS DISEASES
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The invention discloses compounds that are selective α7 nAChR agonists and 5-HT3 antagonists. The compounds are useful for treating many CNS diseases.
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- COMPOUNDS AS RADIOLIGANDS FOR THE DIAGNOSIS OF DISEASE
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Radiolabeled ligands useful as probes for determining the relative abundance, receptor occupancy, and/or function of nicotinic acetylcholine receptors. The compounds of Formula I as described herein are labeled with a radioactive isotopic moiety such as 11C, 18F, 76Br, 123I or 125I. Disorders are diagnosed by administering to a mammal a detectably labeled compound and detecting the binding of that compound to the nAChR. The compounds that have been administered are detected using methods including, but not limited to, position emission topography and single-photon to emission computed tomography. The present invention is useful in diagnosing a wide variety of diseases and disorders as discussed herein.
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- Fused bicyclic-N-bridged-heteroaromatic carboxamides for the treatment of disease
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The invention provides compounds of Formula I: 1These compounds may be in the form of pharmaceutical salts or compositions, may be in pure enantiomeric form or racemic mixtures, and are useful in pharmaceuticals to treat conditions or diseases in which α7 is known to be involved.
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- Azabicyclic compounds for the treatment of disease
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The invention provides compounds of Formula I: wherein Azabicyclo is W is a six-membered heterocyclic ring system having 1-2 nitrogen atoms or a 10-membered bicyclic-six-six-fused-ring system having up to two nitrogen atoms within either or both rings, provided that no nitrogen is at a bridge of the bicyclic-six-six-fused-ring system, and further having 1-2 substitutents independently selected from R3. These compounds may be in the form of pharmaceutical salts or compositions, may be in pure enantiomeric form or racemic mixtures, and are useful in pharmaceuticals to treat diseases or conditions in which α7 is known to be involved.
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- A convenient procedure for the preparation of 3-bromopropiolic esters
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3-Bromopropiolic esters are efficiently prepared by reaction of the corresponding propiolic esters with N-bromosuccinimide in acetone and silver nitrate as catalyst.
- Leroy
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p. 567 - 572
(2007/10/02)
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- SUBSTITUTION DES HALOGENO-1 ALCYNES-1 PAR LES DERIVES ORGANOMETALLIQUES DU CUIVRE. ACCES A UNE NOUVELLE CLASSE DE SYNTHONS: APPLICATION A LA SYNTHESE DU BOMBYKOL
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1-Bromo- and 1-iodo-1-alkynes are alkylated by organocopper(I) compounds.Alkenylcopper(I) derivatives undergo substitution with retention of configuration leading to conjugated and functional enynes, from which conjugated dienes can be obtained.
- Commercon, A.,Normant, J. F.,Villieras, J.
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p. 1215 - 1222
(2007/10/02)
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