cas 116313-85-0, 3-Nitro-4,5-dihydroxybenzaldehyde

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Improved method for demethylation of nitro-catechol methyl ethers
Several nitro-catechol compounds, useful as inhibitors of COMT were obtained in excellent yield and purity via an improved procedure for demethylation of the corresponding methyl ethers using aluminium chloride and pyridine in ethyl acetate.
Learmonth, David A.,Alves, Paula C.
p. 641 - 649
(2002)
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Synthesis of 7-substituted-(2,3-dihydro-1,4-benzodioxin-5-yl)-piperazine
A simple and versatile method for the synthesis of 7-substituted (2,3-dihydro-1,4-benzodioxin-5-yl)-piperazines starting from easy available class of derivatives has been developed. Copyright Taylor & Francis Group, LLC.
Rancati, Fabio,Bromidge, Steven M.,Del Sordo, Simone,La Rosa, Salvatore,Parini, Carlo,Gagliardi, Stefania
p. 2507 - 2520
(2008)
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The inhibition of catechol O-methyltransferase and monoamine oxidase by tetralone and indanone derivatives substituted with the nitrocatechol moiety
The enzymes, catechol O-methyltransferase (COMT) and monoamine oxidase (MAO) are important drug targets, and inhibitors of these enzymes are established therapy for symptomatic Parkinson's disease (PD). COMT inhibitors enhance the bioavailability of levodopa to the brain, and therefore are combined with levodopa for the treatment of motor fluctuations in PD. Inhibitors of the MAO-B isoform, in turn, are used as monotherapy or in conjunction with levodopa in PD, and function by reducing the central degradation of dopamine. It has been reported that 1-tetralone and 1-indanone derivatives are potent and specific inhibitors of MAO-B, while compounds containing the nitrocatechol moiety (e.g. tolcapone and entacapone) are often potent COMT inhibitors. The present study attempted to discover compounds that exhibit dual COMT and MAO-B inhibition by synthesizing series of 1-tetralone, 1-indanone and related derivatives substituted with the nitrocatechol moiety. These compounds are structurally related to series of nitrocatechol derivatives of chalcone that have recently been investigated as potential dual COMT/MAO inhibitors. The results show that 4-chromanone derivative (7) is the most promising dual inhibitor with IC50 values of 0.57 and 7.26 μM for COMT and MAO-B, respectively, followed by 1-tetralone derivative (4d) with IC50 values of 0.42 and 7.83 μM for COMT and MAO-B, respectively. Based on their potent inhibition of COMT, it may be concluded that nitrocatechol compounds investigated in this study are appropriate for peripheral COMT inhibition, which represents an important strategy in the treatment of PD.
de Beer, Andries D.,Legoabe, Lesetja J.,Petzer, Anél,Petzer, Jacobus P.
(2021)
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Ferrocene tagged functional polymer: A robust solid-phase reagent for O-demethylation
Ferrocene tagged functional polymer was synthesized by exploiting the propensity of the Merrifield resin to undergo quaternization with N-ferrocenylmethyl benzimidazole followed by subsequent anion metathesis reaction. The synthesized polymer when employed as a solid-phase reagent for O-demethylation of aryl methyl ethers, showed TON in the range of 7373-8930 and TOF in the range of 279-494 h-1.
Kurane, Rajanikant,Gaikwad, Vipul,Jadhav, Jagannath,Salunkhe, Rajashri,Rashinkar, Gajanan
p. 6361 - 6366,6
(2012)
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Method for producing entacapone
The present invention relates to an entacapone production method, which comprises a nitration reaction, a de-methylation reaction and a condensation reaction. The nitration reaction is completed by glacial acetic acid, vanillin and 65% nitric acid within 3-5 hours; the de-methylation reaction is completed by reaction among nitrovanillin, dichloromethane, tetrabutyl ammonium bromide, anhydrous aluminum chloride and pyridine; and the condensation reaction is completed by reaction among isopropanol, 3,4-dihydroxyl-5-nitro benzaldehyde, N,N-diethyl cyanoacetamide and piperidine. The entacapone production method provided by the invention is high in yield, high in purity and stable in quality.
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(2021/04/10)

Increased Potency and Selectivity for Group III Metabotropic Glutamate Receptor Agonists Binding at Dual sites
A group III metabotropic glutamate (mGlu) receptor agonist (PCEP) was identified by virtual HTS. This orthosteric ligand is composed by an l-AP4-derived fragment that mimics glutamate and a chain that binds into a neighboring pocket, offering possibilities to improve affinity and selectivity. Herein we describe a series of derivatives where the distal chain is replaced by an aromatic or heteroaromatic group. Potent agonists were identified, including some with a mGlu4 subtype preference, e.g., 17m (LSP1-2111) and 16g (LSP4-2022). Molecular modeling suggests that aromatic functional groups may bind at either one of the two chloride regulatory sites. These agonists may thus be considered as particular bitopic/dualsteric ligands. 17m was shown to reduce GABAergic synaptic transmission at striatopallidal synapses. We now demonstrate its inhibitory effect at glutamatergic parallel fiber-Purkinje cell synapses in the cerebellar cortex. Although these ligands have physicochemical properties that are markedly different from typical CNS drugs, they hold significant therapeutic potential.
Selvam, Chelliah,Lemasson, Isabelle A.,Brabet, Isabelle,Oueslati, Nadia,Karaman, Berin,Cabaye, Alexandre,Tora, Amélie S.,Commare, Bruno,Courtiol, Tiphanie,Cesarini, Sara,McCort-Tranchepain, Isabelle,Rigault, Delphine,Mony, Laetitia,Bessiron, Thomas,McLean, Heather,Leroux, Frédéric R.,Colobert, Fran?oise,Daniel, Hervé,Goupil-Lamy, Anne,Bertrand, Hugues-Olivier,Goudet, Cyril,Pin, Jean-Philippe,Acher, Francine C.
supporting information
p. 1969 - 1989
(2018/03/21)

Pyridine Improves Aluminum Triiodide Induced Selective Cleavage of Alkyl o -Hydroxyphenyl Ethers: A Practical and Efficient Procedure for the Preparation of Hydroxychavicol by Demethylation of Eugenol
Demethylation of eugenol with aluminum triiodide is complicated by an unexpected hydrogenation side reaction. The hydrogenation proceeds through a cascade deprotonation, hydroiodination, and hydrogen-halogen exchange process, and can be prevented by suppressing the hydroiodination in advance. A practical demethylation procedure is thus developed that delivers hydryoxychavicol in essentially quantitative yield by using pyridine as an additive. The method is selective towards cleaving alkyl o-hydroxyphenyl ethers and is compatible with a variety of functional groups.
Sang, Dayong,Yao, Ming,Tian, Juan,Chen, Xiaoman,Li, Li,Zhan, Hongju,You, Linhong
p. 138 - 142
(2016/12/26)

Ether bond rupturing method for ortho-hydroxyl phenyl alkyl ether
The invention discloses an ether bond rupturing method for ortho-hydroxyl phenyl alkyl ether. The method comprises the following steps that in a solvent, an ether bond rupturing reaction occurs to ortho-hydroxyl aryl alky ether at the temperature ranging from minus 20 DEG C to the catalyst reflux temperature under the existence of alkali and a catalyst aluminum triiodide, and catechol and derivatives thereof are generated. The method is simple, reaction conditions are simple, and operation is easy; besides, the yield is high, and the applicable ortho-hydroxyl phenyl alkyl ether range is wide.
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Paragraph 0080; 0081; 0082; 0083

(2017/05/27)

Carbodiimides as Acid Scavengers in Aluminum Triiodide Induced Cleavage of Alkyl Aryl Ethers
A practical procedure for the cleavage of alkyl aryl ethers containing labile functional groups has been developed using aluminum triiodide as the ether cleaving reagent. Carbodiimides, typically used as dehydration reagents for the coupling of amines and carboxylic acids to yield amide bonds, are found to be effective hydrogen iodide scavengers that prevent acid-labile groups from deterioration. The method is applicable to variant alkyl aryl ethers such as eugenol, vanillin, ortho -vanillin and methyl eugenol. Suitable substrates are not limited to alkyl o -hydroxyphenyl ethers.
Sang, Dayong,Wang, Jiahui,Zheng, Yun,He, Jianyuan,Yuan, Caili,An, Qing,Tian, Juan
p. 2721 - 2726
(2017/06/13)

Ether bond breakage method for phenylalkyl ethers
The invention discloses an ether bond breakage method for phenylalkyl ethers. The method comprises the step: subjecting the phenylalkyl ethers to an ether bond breakage reaction at the temperature of -20 DEG C to reflux temperature in an organic solvent in the presence of aluminum triiodide and carbodiimide, so as to produce phenols and derivatives thereof. The method is moderate in conditions, simple and convenient in operation, high in yield and wide in applicable phenylalkyl ether range.
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Paragraph 0179-0181

(2017/07/19)

A phenyl alkyl ether ether linkage breaking method (by machine translation)
The invention discloses a phenyl alkyl ether ether linkage breaking method, the method is: in the organic solvent, in the presence of a mineral acid and the aluminium triiodide scavenging agent under the conditions of, phenyl ether in the - 20 °C to reflux temperature lower ether linkage breaking reaction, generating phenol and its derivatives. The mild conditions, the operation is simple, and the yield is high, the applicable phenyl ether range is wide. (by machine translation)
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Paragraph 0105-0107

(2018/04/01)

HETEROCYCLIC COMPOUNDS
The present invention provides a compound represented by the formula (I) wherein each symbol is as defined in the specification, or a salt thereof has an BET family protein inhibitory action, and is useful as an agent for the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases (e.g., rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, atopic dermatitis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic lupus erythematosus etc.), cancer and the like.
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Paragraph 0402

(2016/12/26)

MULTIPLE D2 A(NTA)GONISTS/H3 ANTAGONISTS FOR TREATMENT OF CNS-RELATED DISORDERS
The present invention relates to compounds compound according to Formula (III); and pharmaceutically acceptable salts, hydrates and solvates thereof. These compounds have D2receptor antagonist/(partial) agonist effects and H3antagonistic effects, pharmaceutical compositions thereof, and methods of using them for application in the prophylaxis or treatment of CNS disorders.
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Page/Page column 70; 71

(2015/05/26)

Synthesis and antitumor activity of feruloyl and caffeoyl derivatives This paper is dedicated to Prof. Wei-xiao Hu for his lifelong commitment to mentoring graduate students
We developed two efficient protocols for the synthesis of feruloyl and caffeoyl derivatives from commercial vanillin and veratraldehyde. Pharmacological activities were assessed against a panel of human cancer cell lines in vitro. Most synthesized compounds demonstrated attractive cytotoxicity. Several new compounds demonstrated significant antiproliferative and cytotoxic activities against HeLa and Bewo tumor cell lines. In particular, 5-nitro caffeic adamantyl ester showed broad spectrum of tumor inhibition in 10 cell lines, and reduced tumor weight by 36.7% in vivo when administered at a dose of 40 mg kg-1.
Chen, Hui-Zhen,Chen, You-Bao,Lv, Ya-Ping,Zeng, Fang,Zhang, Juan,Zhou, Yong-Lie,Li, Han-Bing,Chen, Li-Fei,Zhou, Bin-Jie,Gao, Jian-Rong,Xia, Chun-Nian
p. 4367 - 4371
(2015/02/06)

Arylcyanoacrylamides as inhibitors of the Dengue and West Nile virus proteases
The 3-aryl-2-cyanoacrylamide scaffold was designed as core pharmacophore for inhibitors of the Dengue and West Nile virus serine proteases (NS2B-NS3). A total of 86 analogs was prepared to study the structure-activity relationships in detail. Thereby, it turned out that the electron density of the aryl moiety and the central double bond have a crucial influence on the activity of the compounds, whereas the influence of substituents of the amide residue is less relevant. The para-hydroxy substituted analog was found to be the most potent inhibitor in this series with a Ki-value of 35.7 μM at the Dengue and 44.6 μM at the West Nile virus protease. The aprotinin competition assay demonstrates a direct interaction of the inhibitor molecule with active centre of the Dengue virus protease. The target selectivity was studied in a counterscreen with thrombin and found to be 2.8:1 in favor of DEN protease and 2.3:1 in favor of WNV protease, respectively.
Nitsche, Christoph,Steuer, Christian,Klein, Christian D.
p. 7318 - 7337
(2012/01/05)

NOVEL DIHYDROPYRIMIDIN-2(1H)-ONE COMPOUNDS AS S-NITROSOGLUTATHIONE REDUCTASE INHIBITORS
The present invention is directed to novel dihydropyrimidin-2(1H)-one compounds useful as S-nitrosoglutathione reductase (GSNOR) inhibitors, pharmaceutical compositions comprising such compounds, and methods of making and using the same.
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Page/Page column 149

(2011/04/24)

Discovery of a long-acting, peripherally selective inhibitor of catechol- O -methyltransferase
Novel nitrocatechol-substituted heterocycles were designed and evaluated for their ability to inhibit catechol-O-methyltransferase (COMT). Replacement of the pyrazole core of the initial hit 4 with a 1,2,4-oxadiazole ring resulted in a series of compounds endowed with longer duration of COMT inhibition. Incorporation of a pyridine N-oxide residue at position 3 of the 1,2,4-oxadiazole ring led to analogue 37f, which was found to possess activity comparable to entacapone and lower toxicity in comparison to tolcapone. Lead structure 37f was systematically modified in order to improve selectivity and duration of COMT inhibition as well as to minimize toxicity. Oxadiazole 37d (2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4, 6-dimethylpyridine 1-oxide (BIA 9-1067)) was identified as a long-acting, purely peripheral inhibitor, which is currently under clinical evaluation as an adjunct to l-Dopa therapy of Parkinson's disease.
Kiss, László E.,Ferreira, Humberto S.,Torr?o, Leonel,Bonifácio, Maria Jo?o,Palma, P. Nuno,Soares-Da-Silva, Patrício,Learmonth, David A.
experimental part
p. 3396 - 3411
(2010/09/05)

PROCESS FOR THE PREPARATION OF ENTACAPONE
The present invention relates to an improved process for the preparation of Entacapone of formula (I) comprising a step of, condensation of 3,4-dihydroxy-5-nitrobenzaldehyde of formula (II) with N,N-diethylcyanoacetamide of formula (III) in the presence of two component solvent system, a catalyst and optionally a phase transfer catalyst to give Entacapone of formula (I).
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Page/Page column 3-4

(2010/09/18)

Synthesis of 7-Epi (+)-FR900482: An epimer of comparable anti-cancer activity
(Chemical Equation Presented) FR900482 is a potent anti-tumor therapeutic that has been investigated as a replacement candidate for the clinically useful Mitomycin C. Herein, we report synthesis and biological testing of 7-Epi (+)-FR900482, which demonstrates equal potency relative to the natural product against several cancer cell lines. Highlights of this work include utilization of our palladium-catalyzed DYKAT methodology and development of a Polonovski oxidative ring expansion strategy to yield this equipotent epimer in 23 linear steps.
Trost, Barry M.,O'Boyle, Brendan M.
supporting information; experimental part
p. 1369 - 1372
(2009/04/10)

Synthesis of trans-caffeate analogues and their bioactivities against HIV-1 integrase and cancer cell lines
Forty caffeate analogues were synthesized via a convenient method starting from vanillin with moderate to good yields. The testing of biological activity of these compounds against HIV-1 integrase indicates that four compounds: bornyl caffeate, bornyl 2-nitrocaffeate, 5-nitrocaffeic acid and 5-nitrocaffeic acid phenethyl ester (5-nitroCAPE) possess a good HIV integrase inhibitory activity, IC50 19.9, 26.8, 25.0 and 13.5 μM, respectively. Twelve caffeate analogues were tested by MTT assay on growth of human hepatocellular carcinoma BEL-7404, human breast MCF-7 adenocarcinoma, human lung A549 adenocarcinoma and human gastric cancer BCG823 cell lines, respectively. And the best result is IC50 5.5 μM for CAPE against BEL-7404.
Xia, Chun-nian,Li, Hai-bo,liu, Feng,Hu, Wei-xiao
scheme or table
p. 6553 - 6557
(2009/09/06)

NOVEL CRYSTALLINE FORMS OF ENTACAPONE, AND PRODUCTION THEREOF
Disclosed are two novel crystalline forms of entacapone, form C and form D, which represent peripheral and selective COMT inhibitors that can be used for the treatment of Parkinson's disease in combination with levodopa and a decarboxylase inhibitor. Form C is produced by crystallizing entacapone from a mixture of at least one aromatic and at least one aliphatic hydrocarbon. Form D is produced by a) dissolving entacapone in a water-miscible solvent and introducing said solution into water or a mixed aqueous system, or b) dissolving entacapone in a polar aprotic or alcoholic solvent and adding said solution to an aliphatic hydrocarbon which can be mixed with said solvent and in which entacapone is insoluble, or c) crystallizing entacapone in a non-acidic solvent or a solvent mixture containing at least one non-acidic component in the presence of a strong acid, the entacapone being usable as a raw product or, in variant c), as the Knoevenagel condensation product of 3,4-dihydroxy-5-nitro-benzaldehyde and N,N-diethyl-2-cyano-acetamide, which is used in situ. Also disclosed are improvements of said Knoevenagel condensation regarding the catalyst used and regarding the production of the two components thereof, 3,4-dihydroxy-5-nitro-benzaldehyde and N,N-diethyl-2-cyano-acetamide.
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Page/Page column 10

(2008/06/13)

Synthesis of 8-methoxy-1-methyl-1H-benzo[de][1-6]naphthyridin-9-ol (isoaaptamine) and analogues
8-Methoxy-1-methyl-1H-benzo[de][1,6]naphthyridin-9-ol, isoaaptamine, a PKC inhibitor isolated from sponge was synthesized. The synthesis parallels a synthesis of 8,9-dimethoxybenzo[de][1,6]-naphthyridine, aaptamine, but uses a nitromethyl substituent as a precursor of the key 5-(2-aminoethyl)-1H-quinolin-4-one intermediate. The quinolone intermediates were prepared by thermolysis (220-240 °C) of anilinomethylene derivatives of Meldrum's acid. The quinolone intermediates were N-methylated prior to cyclization to the benzo[de][1,6]naphthyridine derivatives. Aaptamine and several analogues of aaptamine and isoaaptamine were prepared including 9-demethylaaptamine, 1-methyl-8-demethylaaptamine, 1-methylaaptamine, and the 8,9-methylenedioxy analogues of aaptamine and 1-methylaaptamine.
Walz,Sundberg
p. 8001 - 8010
(2007/10/03)

Application of ring-closing metathesis to the formal total synthesis of (+)-FR900482
A formal, enantioselective synthesis of the antitumor antibiotic (+)-FR900482 (1) has been completed using an approach that featured the ring-closing metathesis of the diene 37 to give the key intermediate benzazocine 38. Although several initial protecting-group strategies unexpectedly failed at various stages of the endeavor, the successful approach to 1 involved the conversion of commercially available 5-nitrovanillin (10) into the prochiral diol 24. The manipulations of the residues on the aromatic ring of 10 were straightforward, and the diol array in 24 was introduced by the hydride reduction of the malonate 23, which was in turn prepared by a nucleophilic substitution of the triflate 12. Adjustment of alcohol-protecting groups to give 27 and refunctionalization of the aromatic nitro group led to the protected N-allylamine 36. Elaboration of the diol array via a highly stereoselective Grignard addition furnished the diene 37. Ring-closing metathesis of 37 using the Grubbs catalyst 34 cleanly afforded the benzazocine 38. A tactic originally conceived for preparing 42 by introduction of the aziridine ring onto 38 was impractical because the iodo cyclization of the allylic tosylcarbamate 39 was neither efficient nor selective to give 40. Hence, 38 was transformed into 49, which was a key intermediate in Fukuyama's elegant synthesis of racemic FR900482, thereby completing a formal synthesis of the alkaloid. The prochiral diol 24 was enzymatically desymmetrized using Pseudomonas species lipase to give 25 in 94% enantiomeric excess. Inasmuch as subsequent adjustment of the alcohol-protecting groups gave the intermediate 26 (cf the racemic analogue 27) in enantiomerically pure form, an enantioselective synthesis of (+)-FR900482 has also been completed in a formal sense.
Fellows, Ingrid M.,Kaelin Jr., David E.,Martin, Stephen F.
p. 10781 - 10787
(2007/10/03)

Catechol derivatives
Catechol derivatives of the formula STR1 wherein Ra, Rb and Rc have the significance given herein, the ester and ether derivatives thereof which are hydrolyzable under physiological conditions and the pharmaceutically acceptable salts thereof are described and possess valuable pharmacological properties. In particular, they inhibit the enzyme catechol-O-methyltransferase (COMT), a soluble, magnesium-dependent enzyme which catalyses the transference of the methyl group of S-adensoylmethionine to a catechol substrate, whereby the corresponding methyl ethers are formed. Suitable substrates which can be O-methylated by COMT and which can thus be deactivated are, for example, extraneuornal catecholamines and exogeneously-administered therapeutically active substances having a catechol structure. Formula Ia above embraces not only compounds which form part of the invention, but also known compounds; the compounds which form part of the invention can be prepared according to known methods.
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(2008/06/13)

Dihydroxynitrobenzaldehydes and Hydroxymethoxynitrobenzaldehydes: Synthesis and Biological Activity as Catechol-O-methyltransferase Inhibitors
A series of nitro derivatives of dihydroxy- and hydroxymethoxybenzaldehyde was synthesized and tested as potential inhibitors of partially purified pig liver catechol-O-methyltransferase (COMT).All the dihydroxynitrobenzaldehydes prepared were potent inhibitors of COMT, but only one hydroxymethoxynitrobenzaldehyde (3-hydroxy-4-methoxy-5-nitrobenzaldehyde) showed activity as a COMT inhibitor.Although previously reported data showed that the presence of electron-withdrawing substituents at position 5 seemed to be very important for activity as COMT inhibitor, our results suggest that the requirement necessary to enhance the activity of the dihydroxynitrobenzaldehyde derivatives toward COMT is the presence of the nitro group in a position ortho with respect to one hydroxyl group.The assayed compounds showed a reversible inhibition of COMT, which was mixed for all the dihydroxynitro derivatives but noncompetitive for 3-hydroxy-4-methoxy-5-nitrobenzaldehyde when pyrocatechol was the variable substrate and uncompetitive in all the inhibitors with respect to S-adenosyl-L-methionine.
Perez, Rosa A.,Fernandez-Alvarez, Eldiberto,Nieto, Ofelia,Piedrafita, F. Javier
p. 4584 - 4588
(2007/10/02)

PHARMACOLOGICALLY ACTIVE COMPOUNDS, METHODS FOR THE PREPARATION THEREOF AND COMPOSITIONS CONTAINING THE SAME
Pharmacologically active catechol derivatives of formula I I wherein R1 and R2 independently comprise hydrogen, alkyl, acyl, optionally substituted aroyl, lower alkylsulfonyl or alkylcabamoyl or taken together form a lower alkylidene or cycloalkylidene, X comprises an electronegative substituent such as halogen, nitro, cyano, lower alkylsulfonyl, sulfonamido, aldehyde, caboxyl or trifluoromethyl and R3 comprises hydrogen, halogen, hydroxy alkyl, amino, nitro, cyano, trifluoromethyl, lower alkylsulfonyl, sulfonamide, aldehyde, alkyl carbonyl, aralkylidene carbonyl or carboxyl or a group selected from wherein R4 comprises hydrogen, alkyl, cyano, carboxyl or acyl and R5 comprises hydrogen, cyano, carboxyl, alkoxycarbonyl, carboxyalkenyl, nitro, acyl, optionally substituted aroyl or heteroaroyl, hydroxyalkyl or carboxyalkyl or R4 and R5 together form a five to seven membered substituted cycloalkanone ring; -(CO)n(CH2)m-COR wherein n is 0-1 and m is 0-7 and R comprises hydroxy, alkyl, carboxyalkyl, optionally substituted alkene, alkoxy or optionally substituted amino; wherein R8 and R9 independently comprise hydrogen or one of the following optionally substituted groups; alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or together form an optionally substituted piperidyl group; -NH-CO-R10 wherein R10 comprises a substituted alkyl group
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(2008/06/13)