- Synthesis and evaluation of tetrahydroisoquinoline derivatives against Trypanosoma brucei rhodesiense
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Human African Trypanosomiasis (HAT) is a neglected tropical disease caused by the parasitic protozoan Trypanosoma brucei (T. b.), and affects communities in sub-Saharan Africa. Previously, analogues of a tetrahydroisoquinoline scaffold were reported as having in vitro activity (IC50 = 0.25–70.5 μM) against T. b. rhodesiense. In this study the synthesis and antitrypanosomal activity of 80 compounds based around a core tetrahydroisoquinoline scaffold are reported. A detailed structure activity relationship was revealed, and five derivatives (two of which have been previously reported) with inhibition of T. b. rhodesiense growth in the sub-micromolar range were identified. Four of these (3c, 12b, 17b and 26a) were also found to have good selectivity over mammalian cells (SI > 50). Calculated logD values and preliminary ADME studies predict that these compounds are likely to have good absorption and metabolic stability, with the ability to passively permeate the blood brain barrier. This makes them excellent leads for a blood-brain barrier permeable antitrypanosomal scaffold.
- Cullen, Danica R.,Gallagher, Ashlee,Duncan, Caitlin L.,Pengon, Jutharat,Rattanajak, Roonglawan,Chaplin, Jason,Gunosewoyo, Hendra,Kamchonwongpaisan, Sumalee,Payne, Alan,Mocerino, Mauro
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- The evaluation of 1-tetralone and 4-chromanone derivatives as inhibitors of monoamine oxidase
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Abstract: Monoamine oxidase (MAO) is of much clinical relevance, and inhibitors of this enzyme are used in the treatment for neuropsychiatric and neurodegenerative disorders such as depression and Parkinson’s disease. The present study synthesises and evaluates the MAO inhibition properties of a series of 33 1-tetralone and 4-chromanone derivatives in an attempt to discover high-potency compounds and to expand on the structure–activity relationships of MAO inhibition by these classes. Among these series, eight submicromolar MAO-A inhibitors and 28 submicromolar MAO-B inhibitors are reported, with all compounds acting as specific inhibitors of the MAO-B isoform. The most potent inhibitor was a 1-tetralone derivative (1h) with IC50 values of 0.036 and 0.0011?μM for MAO-A and MAO-B, respectively. Interestingly, with the reduction of 1-tetralones to the corresponding alcohols, a decrease in MAO inhibition potency is observed. Among these 1-tetralol derivatives, 1p (IC50 = 0.785?μM) and 1o (IC50 = 0.0075?μM) were identified as particularly potent inhibitors of MAO-A and MAO-B, respectively. Potent compounds such as those reported here may act as leads for the future development of MAO-B specific inhibitors. Graphic abstract: The present study describes the MAO inhibitory activities of a series of 1-tetralone and 4-chromanone derivatives. Numerous high-potency MAO-B specific inhibitors were identified.[Figure not available: see fulltext.].
- Cloete, Stephanus J.,N’Da, Clarina I.,Legoabe, Lesetja J.,Petzer, Anél,Petzer, Jacobus P.
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p. 491 - 507
(2020/10/02)
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- POLYMERIZABLE ABSORBERS OF UV AND HIGH ENERGY VISIBLE LIGHT
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Described are polymerizable high energy light absorbing compounds of formula I: wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, and X are as described herein. The compounds absorb various wavelengths of ultraviolet and/or high energy visible light and are suitable for incorporation in various products, such as biomedical devices and ophthalmic devices.
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Paragraph 0294-0295
(2020/04/10)
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- COMPOUNDS WITH A BENZO[A]CARBAZOLE STRUCTURE AND USE THEREOF
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The invention relates to compounds of general formula (I), and their use for the treatment and diagnosis of degenerative disorders characterised by high cell proliferation and/or tissue degeneration.
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Page/Page column 39-40
(2019/04/10)
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- Process for preparing 7-hydroxy-3,4-dihydro-2H-1-naphthalenone
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The invention discloses a process for preparing 7-hydroxy-3,4-dihydro-2H-1-naphthalenone. The process comprises preparation processes of salting reactions and hydrolysis reactions. The method for preparing 7-hydroxy-3,4-dihydro-2H-1-naphthalenone, which is disclosed by the invention, has the advantages that the fineness of aluminum trichloride is lowly required, only one solvent is used, the solvent is simple to recycle and treat, the production cost is low, the yield is high, the product purity is high, the process is applicable to industrial production.
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Paragraph 0009-0012
(2018/12/03)
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- Rapid probing of the reactivity of P450 monooxygenases from the CYP116B subfamily using a substrate-based method
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Developing a detailed understanding of the reactivity of self-sufficient Type IV P450 monooxygenases, four types of O-methylated substrates were designed as probes, including monoterpenes, cycloalkanes, aromatic compounds and steroids, and the efficiency of their oxyfunction was determined using a colorimetric assay which was based on the reaction between the enzymatic demethylation product, formaldehyde, and Purpald dye. The activity-based fingerprints of new P450RpMO, P450ArMO and P450CtMO (CYP116B members) indicated that CYP116B P450s preferentially oxidize substrates with aromatic components. Moreover, the hydroxylated products were detected based on the preference results. This rapid and efficient strategy, when coupled with GCMS, enables the exploration of the reactivity of other CYP116B members.
- Li, Ren-Jie,Xu, Jian-He,Yin, Yue-Cai,Wirth, Nicolas,Ren, Jiang-Meng,Zeng, Bu-Bing,Yu, Hui-Lei
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p. 8928 - 8934
(2016/10/13)
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- The Synthesis and Evaluation of C7-Substituted α-Tetralone Derivatives as Inhibitors of Monoamine Oxidase
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Based on a previous report that α-tetralone (3,4-dihydro-2H-naphthalen-1-one) is a promising scaffold for the design of highly potent inhibitors of the enzyme, monoamine oxidase, the present study investigates the monoamine oxidase inhibitory properties of a synthetic series of fifteen C7-substituted α-tetralone derivatives. Arylalkyloxy substitution on C7 of the α-tetralone moiety yielded compounds with high inhibition potencies toward the human monoamine oxidase-B isoform with all compounds possessing IC50 values in the submicromolar range (0.00089-0.047 μm). The C7-substituted α-tetralones also were highly potent monoamine oxidase-A inhibitors with thirteen (of fifteen) compounds possessing IC50 values in the submicromolar range (0.010-0.741 μm). The α-tetralones were, however, in each instance selective for monoamine oxidase-B over the monoamine oxidase-A isoform. Dialyses of enzyme-inhibitor mixtures show that, while a representative inhibitor acts as a reversible monoamine oxidase-A inhibitor, inhibition of monoamine oxidase-B is not readily reversed by dialysis. Using a molecular modeling approach, possible binding orientations and interactions of selected α-tetralones with the active sites of the monoamine oxidases are also proposed. This study suggests that C7-substituted α-tetralones are promising monoamine oxidase inhibitors and may represent lead compounds for the development of therapies for Parkinson's disease and depression. C7-Substituted α-tetralones act as high potency reversible inhibitors of human MAO-A and MAO-B. This class of compounds represent promising leads for the development of therapies for Parkinson's disease and depression.
- Legoabe, Lesetja J.,Petzer, Anél,Petzer, Jacobus P.
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p. 895 - 904
(2015/10/06)
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- Synthesis of the dopamine D2/D3 receptor agonist (+)-PHNO via supercritical fluid chromatography: Preliminary PET imaging study with [3-11C]-(+)PHNO
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Carbon-11 labeled (+)-4-[1-11C]propyl-3,4,4a,5,6,10b-hexahydro- 2H-naphtho[1,2-b][1,4]oxazin-9-ol ([1-11C]-(+)-PHNO) is a dopamine D3-preferring agonist radiopharmaceutical used for medical imaging by positron emission tomography (PET). We report the synthesis of (+)-PHNO using supercritical fluid chromatography for enantiomeric resolution of its norpropyl derivative, HNO, followed by propylation. (+)-HNO was used to prepare the radiolabeling precursor, (+)-trans-4-acetyl-9-triisopropylsilyloxy-2,3,4a,5,6, 10b-hexahydro-4H-naphth[1,2b][1,4]oxazine, in 12 steps. Modifications to the labeling procedure were made to ensure consistent preparation of [3- 11C]-(+)-PHNO via [11C]CH3I. A preliminary PET imaging study was carried out with this tracer in an attempt to image dopamine receptors in brown adipose tissue (brown fat) in vivo.
- Shoup, Timothy M.,McCauley, John P.,Lee Jr., David F.,Chen, Rui,Normandin, Marc D.,Bonab, Ali A.,El Fakhri, Georges,Vasdev, Neil
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supporting information
p. 682 - 685
(2014/01/23)
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- 4H-THIENO[3,2-C]CHROMENE-BASED INHIBITORS OF NOTUM PECTINACETYLESTERASE AND METHODS OF THEIR USE
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Compounds that may be used to inhibit Notum Pectinacetylesterase are described, as well as compositions comprising them, and methods of their use to treat diseases and disorders affecting bone.
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Page/Page column 17-18
(2012/12/13)
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- Ferrocene tagged functional polymer: A robust solid-phase reagent for O-demethylation
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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
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p. 6361 - 6366,6
(2012/12/12)
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- SUBSTITUTED NAPHTHALENES
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Disclosed herein are substituted naphthalene-based melatonin (MT) receptor modulators and/or 5-HT receptor modulators of Formula I, process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 37
(2008/12/08)
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- TETRAHYDRONAPHTHYL- PIPERAZINES AS 5-HT1B ANTAGONISTS, INVERSE AGONISTS AND PARTIAL AGONISTS
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The present invention relates to novel tetrahydronaphthylpiperazines derivatives, that are compounds of the formula (I) wherein R1, R2 and R6 are as defined herein, X is CH2 or O, A is a group of the formula (G 1, G2, G2a,G3, G4, G 5 or G6) depicted below, and D is a group of the formula (D) , wherein Y, W and Z are C or N and wherein R7 is as defined herein and their salts and compositions which include selective antagonists, inverse agonists and partial agonists of serotonin 1 (5-HT1) receptors. Compounds of the invention are useful in treating or preventing depression, anxiety, obsessive compulsive disorder (OCD) and other disorders for which a 5-HT1 agonist or antagonist is indicated.
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Page/Page column 29
(2010/02/14)
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- A ring expansion strategy in antiviral synthesis: A novel approach to TAK-779
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A synthesis of TAK-779 that relies on construction of a key carboxylic acid intermediate by a ring expansion with TMSCHN2 is described.
- Smalley Jr., Terrence L.
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p. 1973 - 1980
(2007/10/03)
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- Cleavage of aromatic methyl ethers by chloroaluminate ionic liquid reagents
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We have discovered serendipitously that chloroaluminate ionic liquids can cleave aromatic methyl ethers under surprisingly mild conditions. Three ionic liquids, viz. [TMAH]-[Al2Cl7], [BMIM][Al2Cl7], and [EMIM][Al2Cl6I], and aluminum chloride were compared in the selective demethylation of 4,5-dimethoxyindanone at the 4-methoxy-function. The ionic liquids exhibited a remarkably high selectivity (96:4) in comparison with aluminum chloride (70:30). In addition, the reaction time was drastically shortened when the ionic liquids were used. Interestingly, the three ionic liquids displayed the same reactivity in the demethylation of 4,5-dimethoxyindanone. Considering the lower cost and the bulk availability of the precursors of [TMAH][Al2Cl7], we conclude that this is the most attractive ionic liquid from an industrial point of view. To make the large-scale application of [TMAH][Al2Cl7] feasible, we have developed a safe upscalable method for its preparation. Furthermore, the scope of ether cleavage by the ionic liquid reagent [TMAH][Al2Cl7] was investigated and it was found that aromatic methyl-, al- lyl-, and benzyl-ether cleavage is applicable to a variety of heterocyclic compounds. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
- Kemperman, Gerardus J.,Roeters, Theodorus A.,Hilberink, Peter W.
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p. 1681 - 1686
(2007/10/03)
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- Tricyclic compounds, their production and use
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A compound of the formula: wherein R1 is H or a substituent; m is 1-3; Ar is an aromatic group which may be substituted; X is a bond or a divalent straight-chain group having 1-6 atoms which may be substituted; Y is —S—, —O—, or —N(R2— (R2 is H or a substituent group), Z is —N= or —C(R3)= (R3 is H or a hydrocarbon group), ring A is a benzene ring; ring B is a 5- to 7-membered ring which may be substituted, or a salt thereof is useful for eliciting a prostaglandin I2 receptor agonistic effect.
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- Ionic hydrogenation of dihydroxynaphthalenes with cyclohexane in the presence of aluminum bromide
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Reactions of 1,5-, 1,6-, 1,7-, 2,6-, and 2,7-dihydroxynaphthalenes with cyclohexane in the presence of excess aluminum bromide in methylene bromide quantitatively yield 5-, 6-, and 7-hydroxynaphthalen-1-ones and 6- and 7-hydroxynaphthalen-2-ones, respectively. Tricationic C-protonated complexes are presumed to be reactive intermediates in these processes.
- Ostashevskaya,Koltunov,Repinskaya
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p. 1474 - 1477
(2007/10/03)
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- Steroidal and nonsteroidal sulfamates as potent inhibitors of steroid sulfatase
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Synthetic routes to potent steroidal and nonsteroidal sulfamate-based active site-directed inhibitors of the enzyme steroid sulfatase, a topical target in the treatment of postmenopausal women with hormone-dependent breast cancer, are described. Novel compounds were examined for estrone sulfatase (E1-STS) inhibition in intact MCF-7 breast cancer cells and placental microsomes. Reaction of the sodium salt of estrone with sulfamoyl chloride gave estrone 3-O-sulfamate (EMATE, 2) which inhibits E1-STS activity potently (>99% at 0.1 mM in intact MCF-7 cells, IC50 = 65 pM) in a time- and concentration-dependent manner, suggesting that EMATE is an active site- directed inhibitor. EMATE is also active in vivo orally. 5,6,7,8- Tetrahydronaphthalene 2-O-sulfamate(7) and its N-methylated derivatives (8 and 9) were synthesized, and 7 inhibits the E1-STS activity in intact MCF-7 cells by 79% at 10 μM. 4-Methylcoumarin 7-O-sulfamate (COUMATE) and its derivatives (14, 16, and 18) wee prepared to extend this series of nonsteroidal inhibitors, and COUMATE educes the E1-STS activity in placental microsomes by >90% at 10 μM. Although the orally active COUMATE is less potent than EMATE as an active site-directed inhibitor, it has the important advantage of being nonestrogenic. Analogues (20, 22, 24, 26, 27, 31, 33, 39, and 44) of COUMATE were synthesized to study its structure-activity relationships, and sulfamates of tetralones (46 and 48) and indanones (49, 51, and 53) wee also prepared. While most of these compounds were found to inhibit E1-STS activity less effectively than COUMATE, one analogue, 3,4- dimethylcoumarin 3-O-sulfamate (24), was found to be some 12-fold more potent than COUMATE as an E1-STS inhibitor in intact MCF-7 cells (IC50 = 30 nM for 24, cf. 380 mM for COUMATE). Hence, highly potent sulfamate-based inhibitors of steroid sulfatase, such as EMATE, COUMATE, and 24, possess therapeutic potential and will allow the importance of estrogen formation in breast tumors via the E1-STS pathway to be assessed. A pharmacophore for active site-directed sulfatase inhibition is proposed.
- Woo, L. W. Lawrence,Howarth, Nicola M.,Purohit, Atul,Hejaz, Hatem A. M.,Reed, Michael J.,Potter, Barry V. L.
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p. 1068 - 1083
(2007/10/03)
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- CARBAPENEM DERIVATIVES CONTAINING A BICYCLIC KETONE SUBSTITUENT AND THEIR USE AS ANTI-INFECTIVES
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The present invention relates to carbapenems and provides a compound of the formula (I) wherein R1 is hydroxymethyl, 1-hydroxyethyl or 1-fluoroethyl; R2 is hydrogen or C1-4alkyl; X1 is oxygen or sulphur; and A is of the formula which is optionally substituted on either ring and wherein B is of the formula -CH2-C(=0)-(CH2)n-, -C(=0)-(CH2)n1-, -C(=0)-CH=CH-X2-, -C(=O)CH2CH2X2_(CH2)nC(=O)NH- or -CH=CHC(=O)NH wherein n is 1 or 2, n1 is 2 or 3 and X2 is NH, O or S; and a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, processes for their preparation, intermediates in their preparation, their use as therapeutic agents and pharmaceutical compositions containing them
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- Chemoselective aryl alkyl ether cleavage by thiophenolate anion through its in situ generation in catalytic amount
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Catalytically in sutu generated alkali metal thiophenoxide in NMP (1-melhyl-2-pyrrolidinone) chemoselectively cleaves aryl alkyl elhers in high yields.
- Nayak, Mrinal K.,Chakraborti, Asit K.
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p. 8749 - 8752
(2007/10/03)
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- Novel frameworks for trifluoromethyl ketone and phosphonate TSA inhibitors of type II PLA2
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Design and synthesis of some TSA inhibitors on novel molecular frameworks is described. This TSA analog design culminates in the preparation of the phosphonate 18.
- Garigipati, Ravi S.,Seibel, George,Mayer, Ruth J.,Bolognese, Brian,McCord, Mark,Marshall, Lisa A.,Adams, Jerry L.
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p. 1421 - 1426
(2007/10/03)
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- Carbapenem derivatives containing a bicyclic substituent, process for their preparation, and their use
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The present invention relates to carbapenems and provides a compound of the formula (I) wherein R1is hydroxymethyl, 1-hydroxyethyl or 1-fluoroethyl; R2is hydrogen or C1 4alkyl; X1is oxygen or sulphur; and Ais of the formula which is optionally substituted on either ring and wherein B is of the formula -CH2-C(=O)-(CH2)n-, -C(=O)-(CH2)n1-, -C(=O)-CH=CH-X2-, -C(=O)CH2CH2X2-, -(CH2)nC(=0)NH- or -CH=CHC(=O)NH- wherein n is 1 or 2, n1 is 2 or 3 and X2 is NH, 0 or S; and a pharmaceutically acceptable salt or an in vivohydrolysable ester thereof, processes for their preparation, intermediates in their preparation, their use as therapeutic agents and pharmaceutical compositions containing them.
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- Antimicrobial activity of 5,6-dihydrobenzo-[a]-carbazoles
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A new series of 5,6-dihydrobenzo[a]carbazoles was synthesized, some showing good antibacterial activity. The presence of a dialkylamino ethyl chain on the 2-, 3- or 4-O-substituent seems to be critical for such activity.
- Pappa,Segall,Pizzorno,Radice,Amoroso,Gutkind
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p. 333 - 336
(2007/10/02)
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- Di-and tetrahydronapthyl anti-allergy agents
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This invention relates to compounds of the formula: and the pharmaceutically acceptable salts thereof:, wherein R1 represents straight or branched chain alkyl having 2-4 carbon atoms;, wherein R2 represents hydrogen or straight or branched chain alkyl having 1-6 carbon atoms;, wherein R3 represents hydrogen or straight or branched chain alkyl having 1-3 carbon atoms;, wherein R4 and R10 are different and represent H or n-propyl;, wherein X represents an interger from 2 to 5;, wherein R5 is hydrogen, or acts with R7 to produce an additional carbon--carbon bond between C1 and C2;, wherein R6 represents hydrogen or -Z-COOR9, wherein Z is either absent or represents straight or branched chain alkyl or alkenyl having 1-5 carbon atoms; and R9 represents hydrogen, pharmaceutically acceptable cations, or straight or branched chain alkyl having 1-6 carbon atoms;, wherein R7 is hydrogen, or acts together with R5 to form an additional carbon-carbon bond between C1 and C2, or acts together with R8 to form when R8 is oxygen;, wherein R8 is hydrogen, -O-R11, or oxygen, such that when R8 is oxygen, R8 acts together with R7 to form and, wherein R11 is straight or branched chain alkyl having 1-4 carbon atoms. The di- and tetrahydronaphthyl compounds of this invention are pharmacologically active as leukotriene D4 (LTD4) antagonists and are useful as anti--inflammatory and anti-allergy agents.
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- HYDROXYLATION DU BENZALDEHYDE ET DE CETONES AROMATIQUES PAR LE PEROXYDE D'HYDROGENE EN MILIEU SUPERACIDE
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Benzaldehyde and aromatic ketones are hydroxylated by hydrogen peroxide in SbF5-HF without formation of products arising from Baeyer-Villiger oxidation.
- Gesson, Jean-Pierre,Jacquesy, Jean-Claude,Jouannetaud, Marie-Paule,Morellet, Guy
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p. 3095 - 3098
(2007/10/02)
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- 3-NITROCYCLOALKENONES, SYNTHESIS AND USE AS REVERSE AFFINITY CYCLOALKYNONE EQUIVALENTS
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A partical synthesis of 3-nitrocycloalkenones and their utilization as dienophiles in the Diels-Alder reaction are discribed.The results demonstrate a reverse affinity equivalency between these β-nitro-enones and "cycloalkynones".
- Corey, E. J.,Estreicher, Herbert
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p. 603 - 606
(2007/10/02)
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