- Synthesis of Functionalized Indolines and Dihydrobenzofurans by Iron and Copper Catalyzed Aryl C-N and C-O Bond Formation
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A simple and effective one-pot, two-step intramolecular aryl C-N and C-O bond forming process for the preparation of a wide range of benzo-fused heterocyclic scaffolds using iron and copper catalysis is described. Activated aryl rings were subjected to a highly regioselective, iron(III) triflimide-catalyzed iodination, followed by a copper(I)-catalyzed intramolecular N-or O-arylation step leading to indolines, dihydrobenzofurans, and six-membered analogues. The general applicability and functional group tolerance of this method were exemplified by the total synthesis of the neolignan natural product, (+)-obtusafuran. DFT calculations using Fukui functions were also performed, providing a molecular orbital rationale for the highly regioselective arene iodination process.
- Henry, Martyn C.,Senn, Hans Martin,Sutherland, Andrew
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p. 346 - 364
(2019/01/08)
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- Volatiles from the xylarialean fungus Hypoxylon invadens
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The volatiles emitted by agar plate cultures of the xylarialean fungus Hypoxylon invadens were investigated by use of a closed loop stripping apparatus in combination with GC-MS. Several aromatic compounds were found that could only be identified by comparison to all possible constitutional isomers with different ring substitution patterns. For the set of identified compounds a plausible biosynthetic scheme was suggested that gives further support for the assigned structures.
- Dickschat, Jeroen S.,Wang, Tao,Stadler, Marc
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p. 734 - 746
(2018/04/16)
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- A novel anti-Alzheimer agent inhibiting oligomerization and fibriliation of beta-amyloid protects neuronal cell from Aβ-induced cytotoxicity
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The present invention relates to development of a novel treatment agent for Alzheimerandprime;s disease, having ability of protecting neural cells and inhibiting fibrosis and oligomerization of beta-amyloid. A compound of the present invention is capable of, while maintaining therapeutic effects on Alzheimerandprime;s disease, recovering ability of directly inhibiting oligomerized and fibrous amyloid beta, which is inherent activities of existing curcumin, thereby being useful as a novel inhibitor.COPYRIGHT KIPO 2017
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Paragraph 0064; 0066
(2017/04/25)
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- Dicyanovinyl-substituted J147 analogue inhibits oligomerization and fibrillation of β-amyloid peptides and protects neuronal cells from β-amyloid-induced cytotoxicity
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A series of novel J147 derivatives were synthesized, and their inhibitory activities against β-amyloid (Aβ) aggregation and toxicity were evaluated by using the oligomer-specific antibody assay, the thioflavin-T fluorescence assay, and a cell viability assay in the transformed SH-SY5Y cell culture. Among the synthesized J147 derivatives, 3j with a 2,2-dicyanovinyl substituent showed the most potent inhibitory activity against Aβ42 oligomerization (IC50 = 17.3 μM) and Aβ42 fibrillization (IC50 = 10.5 μM), and disassembled the preformed Aβ42 fibrils with an EC50 of 10.2 μM. Finally, we confirmed that 3j is also effective at preventing neurotoxicity induced by Aβ42-oligomers as well as Aβ42-fibrils.
- Kim, Kyoungdo,Park, Kwang-Su,Kim, Mi Kyoung,Choo, Hyunah,Chong, Youhoon
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supporting information
p. 9564 - 9569
(2015/09/28)
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- Optimization of 4-aminoquinoline/clotrimazole-based hybrid antimalarials: Further structure-activity relationships, in vivo studies, and preliminary toxicity profiling
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Despite recent progress in the fight against malaria, the emergence and spread of drug-resistant parasites remains a serious obstacle to the treatment of infections. We recently reported the development of a novel antimalarial drug that combines the 4-aminoquinoline pharmacophore of chloroquine with that of clotrimazole-based antimalarials. Here we describe the optimization of this class of hybrid drug through in-depth structure-activity relationship studies. Antiplasmodial properties and mode of action were characterized in vitro and in vivo, and interactions with the parasites 'chloroquine resistance transporter' were investigated in a Xenopus laevis oocyte expression system. These tests indicated that piperazine derivatives 4b and 4d may be suitable for coadministration with chloroquine against chloroquine-resistant parasites. The potential for metabolism of the drugs by cytochrome P450 was determined in silico, and the lead compounds were tested for toxicity and mutagenicity. A preliminary pharmacokinetic analysis undertaken in mice indicated that compound 4b has an optimal half-life.
- Gemma, Sandra,Camodeca, Caterina,Sanna Coccone, Salvatore,Joshi, Bhupendra P.,Bernetti, Matteo,Moretti, Vittoria,Brogi, Simone,De Marcos, Maria Cruz Bonache,Savini, Luisa,Taramelli, Donatella,Basilico, Nicoletta,Parapini, Silvia,Rottmann, Matthias,Brun, Reto,Lamponi, Stefania,Caccia, Silvio,Guiso, Giovanna,Summers, Robert L.,Martin, Rowena E.,Saponara, Simona,Gorelli, Beatrice,Novellino, Ettore,Campiani, Giuseppe,Butini, Stefania
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p. 6948 - 6957
(2012/11/07)
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- 1,2,4,5-Tetrahydro-3H-benzazepine compounds, a process for their preparation and pharmaceutical compositions containing them
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Compounds of formula (I): wherein: R1 represents a hydrogen atom or a group selected from cycloalkyl, benzyl and optionally substituted alkyl,R2, R3, R4 and R5 each represent a hydrogen atom or a hydroxy, methyl, —OSO2R10, —OCOR10 or optionally substituted alkoxy group, or R2 and R3, or R3 and R4, or R4 and R5 together form a group —O—(CH2)q—O—, —O—CH═CH—O— or —O—CH═CH—,R6, R7, R8 and R9 each represent a hydrogen atom or an alkoxy group, or R6 and R7, or R7 and R8, or R8 and R9 together form a group —O—(CH2)q—O—-,R10 represents a group selected from linear or branched C1-C6alkoxy, NR11R′11 and optionally substituted alkyl,R11 and R′11 each represent a hydrogen atom or an alkyl group, or R11 and R′1 together with the nitrogen atom carrying them form an optionally substituted, monocyclic or bicyclic, nitrogen-containing heterocycle,X represents O, NH or CH2,m and p each represent 0 or 1,n and q each represent 1 or 2, in racemic form or in the form of optical isomers,and also addition salts thereof with a pharmaceutically acceptable acid. Medicinal products containing the same which are useful in treating various pathologies.
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Page/Page column 11-12
(2009/04/24)
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- Quinoline synthesis: Scope and regiochemistry of photocyclisation of substituted benzylidenecyclopentanone O-alkyl and O-acetyloximes
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Irradiation of substituted 2-benzylidenecyclopentanone O-alkyl and O-acetyloximes in methanol provides a convenient synthesis of alkyl, alkoxy, hydroxy, acetoxy, amino, dimethylamino and benzo substituted annulated quinolines. para-Substituents yield 6-substituted-2,3-dihydro-1H-cyclopenta[b] quinolines with 8-substituted products being obtained from ortho-substituted starting materials. Reactions of meta-substituted precursors are highly regioselective, with alkyl substituents leading to 5-substituted 2,3-dihydro-1H-cyclopenta[b]quinolines and more strongly electron-donating substituents generally resulting in 7-substituted products. 2-Furylmethylene and 2-thienylmethylene analogues yield annulated furo- and thieno-[2,3e]pyridines respectively. Sequential E- to Z-benzylidene group isomerisation and six π-electron cyclisation steps result in formation of a short-lived dihydroquinoline intermediate which spontaneously aromatises by elimination of an alcohol or acetic acid. For 2-benzylidenecyclopentanone O-allyloxime, singlet excited states are involved in both steps. The Royal Society of Chemistry 2007.
- Austin, Mark,Egan, Oliver J.,Tully, Raymond,Pratt, Albert C.
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p. 3778 - 3786
(2008/10/09)
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- COMPOUNDS WHICH INHIBIT BETA-SECRETASE ACTIVITY AND METHODS OF USE THEREOF
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The present invention provides novel beta-secretase inhibitors of the general formula (I), where the variables A1, A2, L1, L2, L3, R1, R2, R3, R4, R5, R6 and R7 are as defined in the claims, a method for their use in treating Alzheimer's disease, and methods for their use in reducing memapsin 2 catalytic activity.
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Page/Page column 65
(2008/06/13)
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- Compositions containing aromatic aldehydes and their use in treatments
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Disclosed are pharmaceutical and cosmetic compositions containing aromatic aldehyde compounds. Some of the disclosed compositions are useful as topical therapeutics for treating inflammatory dermatologic conditions. Some of the compositions are useful in transdermal and other systemic dose forms for treating other inflammatory conditions in mammals.
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- NOVEL IMIDAZOLES WITH ANTI-INFLAMMATORY ACTIVITY
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Compounds of formula I wherein: one of X or Y represents N and the other represents C; R1 represents hydrogen, methyl, halogen, cyano, nitro, -CHO, -COCH3 or -COOR4; R2 represents optionally-substituted aryl or heteroaryl; R3 represents C1-8 alkyl, C1-8 haloalkyl or -NR4R6; R4 represents hydrogen, C1-8 alkyl or arylC0-8 alkyl; R6 represents hydrogen, C1-8 alkyl, arylC1-8 alkyl, -COR8 or -COOR8; R8 represents C1-8 alkyl or C1-8 haloalkyl; aryl in the above definitions represents phenyl or naphthyl; and heteroaryl in the above definitions represents pyridine, pyrazine, pyrimidine or pyridazine, which can be optionally fused to a benzene ring. These compounds are useful as cyclooxygenase-2 inhibitors.
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- Baker's yeast-mediated enantioselective synthesis of the bisabolane sesquiterpenes (+)-curcuphenol, (+)-xanthorrhizol, (-)-curcuquinone and (+)-curcuhydroquinone
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Fermenting baker's yeast converts the unsaturated aldehydes 5a-c into the saturated alcohols 6a-c, respectively. The microbial saturation of substrates adsorbed on a nonpolar resin proceeds in high chemical yields and shows complete enantioselectivity in the formation of the (S)-(+) isomers. Enantiopure 6a-c are versatile chiral building blocks for the synthesis of bisabolane sesquiterpenes. Their usefulness is shown in the preparation of (S)-(+)-curcuphenol, (S)-(+)-xanthorrhizol, (S)-(-)-curcuquinone and (S)-(+)-curcuhydroquinone. The Royal Society of Chemistry 2000.
- Fuganti, Claudio,Serra, Stefano
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p. 3758 - 3764
(2007/10/03)
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- 3-Alkoxy Substituted Oligo- and Poly(1,4-phenyleneethenylene)s
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The 3-alkoxy-4-methylbenzaldehydes (3a-e) can be obtained by alkylation of the hydroxy compound 1.Reaction with aniline yields the azomethines (4a-e) which enter in an alkaline medium a polycondensation to the title compounds 5a-e.Contrary to the 2-substituted educts, a competitive intramolecular condensation process is principally not possible.Benzoylation of 1 furnisches 3f.However, the corresponding Schiff base 4 f is not capable of a condensation reaction because the ester group is cleaved.
- Kretzschmann, H.,Meier, H.
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p. 255 - 259
(2007/10/02)
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- Introduction of a putative dopaminergic prodrug moiety into a 6,7-substitution pattern characteristic of certain 2-aminotetralin dopaminergic agonists
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On the basis of the premise that the dopaminergic agonist profile of 2-(di-n-propylamino)-5-hydroxy-6-methyltetralin (1a) is due to in vivo oxidation of the 6-methyl moiety and that 1a may represent a novel prodrug strategy, the vicinal methyl-hydroxyl substitution pattern was incorporated into the 6- and 7-positions of 2-(di-n-propylamino)tetralin to give the 6-methyl-7-hydroxy and 6-hydroxy-7-methyl isomers 8 and 9, respectively. A multistep synthetic approach was devised which permitted preparation of target molecules 8 and 9. Pharmacological data revealed that both target compounds exhibit modest dopamine-like effects in the cardioaccelerator nerve assay in the cat, but neither appeared to be metabolically activated as was the case with 1a. The effects of 9 (but not of 8) were antagonized by pretreatment with haloperidol. Thus, the 5-hydroxy-6-methyl substition pattern in the 2-aminotetralins remains unique as a dopaminergic agonist prodrug structure.
- Cannon,True,Long,Bhatnagar,Leonard,Flynn
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p. 2210 - 2214
(2007/10/02)
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- Pharmaceutically active phenylcarboxylic acid derivatives
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Compounds which antagonize the slow-reacting substance of anaphylaxis or components thereof, e.g., leukotrienes, in warm blooded animals as well as intermediates and methods for their preparation, pharmaceutical compositions and methods for their administration. The compounds are diphenyl carboxylic acids with particular linking groups between the individual phenyl rings and the carboxylic acid moiety. Particular utilities are to relieve asthma and inflammation in man.
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- Ortho Metalation Directed by α-Amino Alkoxides
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The addition of aromatic aldehydes to certain lithium dialkylamides in benzene or tetrahydrofuran gave α-amino alkoxides which were ortho lithiated with excess n-butyllithium.Subsequent alkylation and hydrolysis provided ortho-substituted aromatic aldehydes via a one-pot reaction.The ortho metalation of α-amino alkoxides derived from 1- and 2-naphthaldehyde and various substituted benzaldehydes was examined.When N,N,N'-trimethylethylenediamine was used as the amine component of the α-amino alkoxide, metalation could be carried out at lower temperatures.This rate increase is due to an intramolecular TMEDA-like assisted metalation.The synthetic utility of this ortho metalation, including how varying the amine component of the α-amino alkoxide affects the regiochemistry and metalation rate, is discussed.
- Comins, Daniel L.,Brown, Jack D.
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p. 1078 - 1083
(2007/10/02)
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- Studies on the Synthesis of Heterocyclic Compounds. Part 832. A Simple and Efficient Synthesis of Apomitomycin Derivatives; a Potential Intermediate for Mitomycin Synthesis
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Condensation of pyrrolidine-2-thione (21) with methyl α-bromo-(2-bromo-4,5-dimethoxyphenyl)acetate (15) gave methyl (Z)-α-(2-bromo-4,5-dimethoxyphenyl)-α-pyrrolidin-2-ylideneacetate (25) in high yield.Several other methyl (Z)-α-aryl-α-acetates (26)-(31) were also synthesised in good yields from reaction of the corresponding phenylacetates (15), (12), and (13) with trans-3-acetoxy-4-(N-ethoxycarbonyl-N-methylamino)pyrrolidine-2-thione (20).Treatment of compounds (25)-(31) with sodium hydride and copper(I) bromide in dimethylformamide afforded methyl 2,3-dihydro-6,7-dimethoxy-1H-pyrroloindole-9-carboxylate (34) and the methyl (+/-)-trans-1-acetoxy-2-(N-ethoxycarbonyl-N-methylamino)-2,3-dihydro-1H-pyrroloindole-9-carboxylates (35)-(37) in good yields.Methyl (+/-)-trans-1-acethoxy-2-(N-ethoxycarbonyl-N-methylamino)-2,3-dihydro-7-methoxy-6-methyl-1H-pyrroloindole-9-carboxylate (36) was converted into the 5,8-quinone (3), via the 8-nitro-compound (38).
- Kametani, Tetsuji,Kigawa, Yoshio,Nemoto, Hideo,Ihara, Masataka,Fukumoto, Keiichiro
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p. 1607 - 1613
(2007/10/02)
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