- The synthesis of 3-diazo-2-nitromethylenepiperidine
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The synthesis of 3-diazo-2-nitromethylenepiperidine, in six steps from 2-piperidone, is reported. This is the first compound described which contains the 3-diazo-1-nitropropene function. The title compound is stable enough to be isolated and characterised in gram quantities using standard organic chemistry techniques and was used to prepare some 5-aza-spiro[2.5]octane and 4,5,6,7-tetrahydro-1H-pyrazolo-[4,3-b]pyridine derivatives.
- Hutchinson, Ian S.,Matlin, Stephen A.,Mete, Antonio
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- Synthetic studies on the ceveratrum alkaloid skeleton
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1-(2-Cyclohexenyl-1-carbonyl)-piperidine-2-carboxyaldehyde oxime (23) was prepared in 5 steps from pyridine-2-carboxaldehyde. Oxidation with NaOCl afforded the corresponding nitrile oxide which cyclized to give a 1:1 ratio of diastereomers 2aα,3,4,5,5aα,9,10,11aβ,11cα-decahydro-6H,8H-[1,2]benzisoxazolo[3, 4-ab]quinolizin-6-one (24A) and 2aα,3,4,5,5aα,9,10,11aα,11cα-decahydro-6H,8H-[1,2]benzisoxazolo[3, 4-ab]quinolizin-6-one (24B) in a best yield of 30%.
- Jones, Keith,Newton, Roger F.,Yarnold, Christopher J.
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- FUSED BICYCLIC COMPOUNDS AND USES THEREOF IN MEDICINE
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Fused bicyclic compounds and uses thereof in medicine. In particular, provided are fused bicyclic compounds used as ASK1 active regulator and and use of the compounds in the manufacture of a drug for treating a disease regulated by ASK1. Further provided are a pharmaceutical composition and a method of treating a disease regulated by ASK1 comprising administering the compounds or pharmaceutical composition thereof.
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Paragraph 00178
(2019/03/05)
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- Sulfinate and Carbene Co-catalyzed Rauhut–Currier Reaction for Enantioselective Access to Azepino[1,2-a]indoles
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A carbene and sulfinate co-catalyzed intermolecular Rauhut–Currier reaction between enals and nitrovinyl indoles is disclosed. The carbene catalyst activates the enal and the sulfinate co-catalyst activates the nitrovinyl indole. Both activation processes are realized via the formation of covalent bonds between the catalysts and substrates to generate catalyst-bound intermediates. The dual catalytic reaction affords azepino[1,2-a]indole products with excellent stereoselectivity. Our study demonstrates the unique involvement of sulfinate as an effective nucleophilic catalyst in activating electron-deficient alkenes for asymmetric reactions. This dual catalytic approach should also encourage future explorations of both sulfinate and carbene catalysts for new reactions.
- Wu, Xingxing,Zhou, Liejin,Maiti, Rakesh,Mou, Chengli,Pan, Lutai,Chi, Yonggui Robin
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supporting information
p. 477 - 481
(2018/12/14)
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- Synthesis of [1,2-A]-fused tricyclic dihydroquinolines by palladiumcatalyzed intramolecular C-N cross-coupling of polarized heterocyclic enamines
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A simple methodology for [1,2-A]-fused tricyclic dihydroquinolines is established. The key ste of the methodology is an intramolecular Buchwald-Hartwig amination reaction of suitabl halogenated (both bromo and chloro) cyclic enaminoketones, enaminoesters and enaminonitrile with various ring size (from five-to seven-membered). Optimal reaction conditions (palladiu source, base, ligand) depend on the ring size of the starting enamine, giving 65-98% yield of th tricyclic product. A treatment of the products with perchloric acid gives respective quinoliniu perchlorates.
- Bro?, B?etislav,R??i?ková, Zdeňka,?im?nek, Petr
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supporting information
p. 118 - 141
(2016/10/22)
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- Pyrrolopyrimidine Derivatives as Novel Inhibitors of Multidrug Resistance-Associated Protein 1 (MRP1, ABCC1)
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Five series of pyrrolo[3,2-d]pyrimidines were synthesized and evaluated with respect to potency and selectivity toward multidrug resistance-associated protein 1 (MRP1, ABCC1). This transport protein is a major target to overcome multidrug resistance in cancer patients. We investigated differently substituted pyrrolopyrimidines using the doxorubicin selected and MRP1 overexpressing small cell lung cancer cell line H69 AR in a calcein AM and daunorubicin cell accumulation assay. New compounds with high potency and selectivity were identified. Piperazine residues at position 4 bearing large phenylalkyl side chains proved to be beneficial for MRP1 inhibition. Its replacement by an amino group led to decreased activity. Aliphatic and aliphatic-aromatic variations at position 5 and 6 revealed compounds with IC50 values in high nanomolar range. All investigated compounds had low affinity toward P-glycoprotein (P-gp, ABCB1). Pyrrolopyrimidines with small substituents showed moderate inhibition against breast cancer resistance protein (BCRP, ABCG2).
- Schmitt, Sven Marcel,Stefan, Katja,Wiese, Michael
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p. 3018 - 3033
(2016/05/19)
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- Dihydro pyridine compound, its composition, preparation method and use
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Disclosed dihydropyridine compounds are the compounds possessing the following general formula (I) as shown in the specification, wherein R1 is selected from hydrogen, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic groups, substituted heterocyclic groups, ester group and amide group; R2 is selected from hydrogen, cyanogroup, alkyl, substituted alky, alkenyl, substituted alkenyl and acyl; or R2 and R3 form a fused ring; R3 is selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R3 and R2 or R4 form a fused ring; R4 is selected from hydrogen, alkyl and substituted alkyl; or R4 and R3 or R5 form a fused ring; R5 is selected form alkyl, substituted alky, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R5 and R4 form a fused ring. The invention also discloses a preparation method of the compounds of the general formula (I), compositions containing the compounds of the general formula (I), and applications of the compositions to medicaments for treating cancers.
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Paragraph 0321 - 0323
(2016/10/10)
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- A simple, enaminone-based approach to some bicyclic pyridazinium tetrafluoroborates
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Easily obtainable cyclic enaminones (piperidin-2-ylidenealkanones) can be transformed into substituted bicyclic pyridazinium tetrafluoroborates upon treatment with corresponding diazonium salts. The transformation can be performed either in a one-pot way or in a two-step process with the isolation of single azo-coupled enaminone as the intermediate. The former method is superior. Under the optimized conditions, a number of pyridazinium salts substituted with both electron-donating and electron-withdrawing substituents was easily synthesized. A mechanism of the formation of the pyridazinium salts is suggested. A partial drawback is the possibility of the formation of a mixture of products when using a different diazonium salt in each step due to a reversibility of the azo coupling. This can be suppressed by using a more reactive diazonium salt before a less reactive one.
- Josefik, Frantisek,Svobodova, Marketa,Bertolasi, Valerio,Simunek, Petr
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supporting information
p. 1463 - 1471
(2013/08/23)
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- Highly β-regioselective Friedel-Crafts aminoalkylation of pyrroles with cyclic perfluoroalkylated imines
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A Friedel-Crafts-type alkylation reaction was studied between various pyrroles and α-polyfluoroalkylated cyclic imines that were activated by Lewis acids. The reaction proceeded under mild conditions and provided a high yielding synthesis of α-CF3-substituted pyrrolidines and piperidines as well as seven-membered analogues that contained a pyrrole ring. The unpredictably high β-selectivity for the aminoalkylation of both 1H-pyrrole and N-substituted pyrrole was observed as a result of a thermodynamically-controlled electrophilic substitution reaction. The computational data are in full agreement with the experimental results, which confirmed the observed regioselectivity as a result of the lower energy of the β-substituted pyrroles that contain α-trifluoromethyl-substituted pyrrolidine, piperidine, and azepane rings. Trifluoromethyl-substituted cyclic imines were activated by various Lewis acids and underwent a reaction with pyrrole derivatives. An unpredictable β-selectivity was observed. The regioselectivity of the aminoalkylation was explained by computation data, which also confirmed the isomerization of the α isomer into the β isomer. Copyright
- Shmatova, Olga I.,Shevchenko, Nikolay E.,Balenkova, Elisabeth S.,Roeschenthaler, Gerd-Volker,Nenajdenko, Valentine G.
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p. 3049 - 3058
(2013/06/27)
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- SUBSTITUTED IMIDAZOHETEROCYCLE DERIVATIVES
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The present invention provides substituted imidazoheterocycles having the general structure of formula (I), wherein Y is chosen from -O-, -OCRgRh-, -CRgRhO-, -CRgRh-, -(CRgRh)2-, -NRi-, -CRgRhNRi- and -NRiCRgRh-. Also provided are pharmaceutically acceptable salts, acid salts, hydrates, solvates and stereoisomers of the compounds of formula I. The compounds are useful as modulators of cannabinoid receptors and for the prophylaxis and treatment of cannabinoid receptor-associated diseases and conditions, such as pain, inflammation and pruritis.
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Page/Page column 30-31
(2010/07/02)
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- α′-Hydroxyenones as mechanistic probes and scope-expanding surrogates for α,β-unsaturated aldehydes in N-heterocyclic carbene-catalyzed reactions
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N-heterocyclic carbene-catalyzed reactions of α,β-unsaturatedaldehydes and a variety of electrophiles allow the facile preparation o f a diverse array of annulation products including trisubstituted cyclopentenes, γ-lactams, and bicyclic β-lactams. The substrate scope of these reactions, however, is limited by the difficulties of preparing the starting α,β-unsaturated aldehydes. We now report that α′- hydroxyenones, which can be prepared in a single convenient step from aromatic and heteroaromatic aldehydes, can serve as efficient surrogates for enals in the annulation reactions. This protocol allows the facile preparation and use of substrates bearing nitrogen heterocycles. These reagents have also allowed us to demonstrate that, in contrast to other classes of aldehydes, the formation of the Breslow intermediate from enals and N-heterocyclic carbenes is irreversible under the reaction conditions.
- Chiang, Pei-Chen,Rommel, Michael,Bode, Jeffrey W.
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supporting information; experimental part
p. 8714 - 8718
(2009/10/23)
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- Potent antimalarial activity of 2-aminopyridinium salts, amidines, and guanidines
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We describe the design, synthesis, and antimalarial activity of 60 bis-tertiary amine, bis-2(1H)-imino-heterocycle, bis-amidine, and bis-guanidine series. Bis-tertiary amines with a linker from 12 to 16 methylene groups were active against the in vitro growth of Plasmodium falciparum within the 10 -6-10-7 M concentration range. IC50 decreased by 2 orders of magnitude for bis-2-aminopyridinium salts, bis-amidines, and bis-guanidines (27 compounds with IC50 a over 12.5. Maximal activity occurs for bis-2-aminopyridinium, two C-duplicated bis-amidines, and three bis-guanidines, with IC50 values lower than 1 nM. In comparison to similar quaternary ammonium salts, amidinium compounds have distinct structural requirements for antimalarial activity and likely additional binding opportunities on account of their hydrogen-bond-forming properties.
- Calas, Michèle,Ouattara, Mahama,Piquet, Gilles,Ziora, Zyta,Bordat,Ancelin, Marie L.,Escale, Roger,Vial, Henri
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p. 6307 - 6315
(2008/09/16)
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- Adamantyl triazoles as selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1
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Adamantyl triazoles were identified as selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). They are active both in in vitro and in in vivo pharmacodynamic models. The synthesis and structure-activity relationships of these inhibitors are presented.
- Olson, Steven,Aster, Susan D.,Brown, Kai,Carbin, Linda,Graham, Donald W.,Hermanowski-Vosatka, Anne,LeGrand, Cheryl B.,Mundt, Steven S.,Robbins, Michael A.,Schaeffer, James M.,Slossberg, Llnon H.,Szymonifka, Michael J.,Thieringer, Rolf,Wright, Samuel D.,Balkovec, James M.
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p. 4359 - 4362
(2007/10/03)
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- PYRROLOPYRIMIDINE DERIVATIVES USEFUL AS MODULATORS OF MULTIDRUG RESISTANCE
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A compound which is a pyrrolopyrimidine of formula (I) wherein: R1 is selected from R9 and halogen; R2 is NR6R7; R3 is selected from H, C1-C6 alkyl which is unsubstituted or substituted and -(CH2) nAr; R4 is selected from H, C1-C6 alkyl and -(CH2)? Ar; or R3 and R4 form, together with the N and C atoms to which they are attached, a fused five-, six-, seven- or eight-membered N-containing saturated ring which is unsubstituted or substituted; R5 is selected from CN, C02R9,C(O)NR10R11, -(CH2)nOH, -(CH2)nR10Rn, -C=CH, -C(S)NR10R11, -C(NH2)=NOR9, -C(R9)=NOR9, -C(NH2)NH, -C(O)R9 and an unsaturated 5- or 6-membered heterocyclic group which contains 1, 2 or 3 heteroatoms selected from N, O and S and which is unsubstituted or substituted; R6 and R7, which are the same or different, are selected from C1-C6 alkyl which is unsubstituted or substituted, -(CH2)nX and -(CH2)nAr; or R6 and R7 form, together with the nitrogen atom to which they are attached, a saturated five-, six-, seven- or eight-membered heterocyclic group which contains one nitrogen atom and 0 or from 1 to 3 additional heteroatoms selected from N, O and S, which is unsubstituted or substituted and which optionally contains one or two bridgehead atoms; R10and R11,which are the same or different, are selected from H, C1-C6 alkyl which is unsubstituted or substituted, -(CH2)nC3-C10 cycloalkyl and -(CH2)nAr; or R10 and R11 form, together with the nitrogen atom to which they are attached, a saturated five or six membered heterocyclic group which contains a nitrogen atom and 0 or from to 3 additional heteroatoms selected from O, S and N, which is unsubstituted or substituted and which is optionally fused to a benzene ring which is unsubstituted or substituted; n is the same or different when more than one is present within a given substituent group and is 0 or an integer of from 1 to 6; X is selected from -CN, -C02R9 and -NR10R11; R9 is the same or different when more than one is present within a given substituent group and is selected from -H, -QAr, -(CH2) nAr, C1-C6 alkyl which is unsubstituted or substituted and -(CH2) nC3-C10cycloalkyl, wherein the cycloalkyl moiety is optionally fused to a benzene ring which is unsubstituted or substituted; Q is C2-C6 alkenylene or alkynylene; and Ar is an unsaturated C6-C10 membered carbocyclic group or an unsaturated 5-11 membered heterocyclic group, which groups are unsubstituted or substituted; or a pharmaceutically acceptable salt thereof. These compounds have activity as inhibitors of MRP (multidrug resistant protein) and may thus be used to modulate multidrug resistance, for instance in potentiating the cytotoxicity of a chemotherapeutic agent.
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- THE R-ISOMER OF BETA AMINO ACID COMPOUNDS AS INTEGRIN RECEPTOR ANTAGONISTS DERIVATIVES
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The present invention relates to a class of compounds represented by the Formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising compounds of the Formula (I), and methods of selectively inhibiting or antagonizing the αVβ3 and/or the αV β5 integrin without significantly inhibiting the αV β6 integrin
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Page/Page column 95
(2010/02/07)
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- Catharsitoxins from the Chinese remedy qiung laug
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Novel imidazole compounds, catharsitoxins A, B, C, D, E and F, were isolated from the Chinese remedy qiung laug. Their structures were determined by 2D NMR. To confirm their structures and to ensure an adequate supply for further biological studies, catharsitoxins A and D were synthesized.
- Suenaga, Kiyotake,Shimogawa, Hiroki,Nakagawa, Satoru,Uemura, Daisuke
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p. 7079 - 7081
(2007/10/03)
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- Synthesis and antimuscarinic activity of some N-(4-dimethylaminomethyl- 2-phenyl-[1,3]dioxolan-2-ylmethyl)lactam methiodides
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A series of 1,3-dioxolane-based ligands, having a lactam function were synthesized and tested as potential muscarinic antagonists. The compounds display moderate affinity for the three receptor subtypes M1-M3, with significant selectivity for the M1-M3 over the M2 subtype.
- Malmusi, Luca,Franchini, Silvia,Mucci, Adele,Angeli, Piero,Gulini, Ugo,Marucci, Gabriella,Brasili, Livio
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p. 499 - 509
(2007/10/03)
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- Cyclic amidine analogs as inhibitors of nitric oxide synthase
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Disclosed herein are compounds of Formula I STR1 and pharmaceutically acceptable salts thereof which have been found useful in the treatment of nitric oxide synthase mediated diseases and disorders, including neurodegenerative disorders, disorders of gastrointestinal motility and inflammation. These disease and disorders include hypotension, septic shock, toxic shock syndrom, hemodialysis, IL-2 therapy such as in cancer patients, cachexia, immunosuppression such as in transplant therapy, autoimmune and/or inflammatory indications including sunburn or psoriasis and respiratory conditions such as bronchitis, asthma, and acure respiratory distress (ARDS), myocarditis, heart failure, atherosclerosis, arthritis, rheumatoid arthritis, chronic or inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosis (SLE), ocular conditions such as ocular hypertension and uveitis, type 1 diabetes, insulin-dependent diabetes mellitus and cystic fibrosis. Compounds of Formula I are also usful in the treatment of hypoxia, hyperbaric oxygen convulsions and toxicity, dementia, Sydenham's chorea, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, mulitple sclerosis, Korsakoff's disease, imbecility related to cerebral vessel disorder, ischemic brain edema, sleeping disorders, schizophrenia, depression, PMS, anxiety, drug addiction, pain, migraine, immune complex disease, as immunosupressive agents and for preventing or reversing tolerance to opiates and diazepines.
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