- Intramolecular Reductive Cyclization of o-Nitroarenes via Biradical Recombination
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A visible-light-induced/thiourea-mediated intramolecular cyclization of o-nitroarenes under mild conditions is realized for the first time, which provides an efficient and environmentally friendly way to access pharmaceutical relevant quinazolinone derivatives. The reaction can be easily extended to gram level by using a continuous-flow setup with high efficiency. Mechanistic investigation including control experiments, transient fluorescence, UV-vis spectra, and DFT calculations suggests that the formation of active biradical intermediates via intramolecular single electron transfer (SET) is key stage in the catalytic cycle.
- Lu, Cong,Su, Zhishan,Jing, Dong,Jin, Songyang,Xie, Lijuan,Li, Liangrui,Zheng, Ke
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p. 1438 - 1443
(2019/03/07)
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- Light-Driven Intramolecular C?N Cross-Coupling via a Long-Lived Photoactive Photoisomer Complex
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Reported herein is a visible-light-driven intramolecular C?N cross-coupling reaction under mild reaction conditions (metal- and photocatalyst-free, at room temperature) via a long-lived photoactive photoisomer complex. This strategy was used to rapidly prepare the N-substituted polycyclic quinazolinone derivatives with a broad substrate scope (>50 examples) and further exploited to synthesize the natural products tryptanthrin, rutaecarpine, and their analogues. The success of gram-scale synthesis and solar-driven transformation, as well as promising tumor-suppressing biological activity, proves the potential of this strategy for practical applications. Mechanistic investigations, including control experiments, DFT calculations, UV-vis spectroscopy, EPR, and X-ray single-crystal structure of the key intermediate, provides insight into the mechanism.
- Jing, Dong,Lu, Cong,Chen, Zhuo,Jin, Songyang,Xie, Lijuan,Meng, Ziyi,Su, Zhishan,Zheng, Ke
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p. 14666 - 14672
(2019/09/06)
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- UREA PEPTOID BORIC ACID COMPOUND, PHARMACEUTICAL COMPOSITION THEREOF, PREPARATION METHOD THEREFOR, AND USES THEREOF
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The present invention provides a urea peptidomimetic boronic compound and pharmaceutical compositions thereof, their preparative methods and uses. The compounds are represented by the following formula (I).
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Paragraph 0171
(2018/09/08)
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- Tyrosine Kinase Inhibitor And Uses Thereof
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Disclosed is a compound of Formula (I) or a pharmaceutically acceptable salt, ester, or solvate thereof, or their stereoisomers, which can be used as tyrosine kinase inhibitor. Also disclosed is a method for preparing the compound, a pharmaceutical composition and a kit comprising the compound, and uses of the compound. The compound can be used as tyrosine kinase inhibitor, or can be used to reduce or inhibit activity of EGFR or mutant thereof, such as EGFR mutant comprising T790M mutation, in a cell, or to treat and/or prevent a disease associated with overactivity of EGFR, such as cancer.
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- Synthesis and in vitro evaluation of tetrahydroisoquinolines with pendent aromatics as sigma-2 (σ2) selective ligands
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5-Bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2, 3-dimethoxybenzamide 1 is a potent and selective σ2 receptor ligand suitable for further development. A series of new analogues, incorporating a variety of isoquinoline and carboxylic acid moieties, linked together with either a linear or cyclic amine spacer have been synthesised and assessed for their σ1/σ2 binding affinity and selectivity. Compounds with a rigid piperidine spacer gave Ki values for the σ2 receptor between 8.7-845 nM. Changing the configuration of the methoxy groups on the isoquinoline moiety resulted in molecules with σ2Ki values of 4.4-133 nM whereas varying the length and flexibility of the carbon spaces gave σ2Ki values 0.88-15.0 nM, some of the most active, selective σ2 ligands to date. Thus, the flexibility and length of the carbon linker and the carboxylic acid moiety are confirmed to be key to the exceptional binding affinity and selectivity for this active series. Additionally, the incorporation of a halogen on selected carboxylic acid moieties provided a convenient strategy for the introduction of a radiohalogen for applications in pharmacological and imaging studies.
- Ashford, Mark E.,Nguyen, Vu H.,Greguric, Ivan,Pham, Tien Q.,Keller, Paul A.,Katsifis, Andrew
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supporting information
p. 783 - 794
(2014/01/23)
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- BICYCLIC INHIBITORS OF ALK
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The present invention relates to compounds of formula (1) or pharmaceutical acceptable salts, wherein R1, X, Y, Z, A, B, G1, and n are defined in the description. The present invention relates also to compositions containing said compounds which are useful for inhibiting kinases such as ALK and methods of treating diseases such as cancer.
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- NOVEL MONOAMINE RE-UPTAKE INHIBITOR
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The present invention relates to novel compounds of Formula (I), their pharmaceutically acceptable derivatives, tautomeric forms, stereoisomers including R and S isomers, polymorphs, prodrugs, metabolites, salts or solvates thereof. The invention also rel
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- Synthesis and in vitro opioid receptor functional antagonism of analogues of the selective kappa opioid receptor antagonist (3R)-7-hydroxy-N-((1S)-1- {[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl) -1,2,3,4-tetrahydro-3-is
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In previous structure-activity relationship (SAR) studies, we identified (3R)-7-hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1- piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3- isoquinolinecarboxamide (JDTic, 1) as the first poten
- Cai, Tingwei Bill,Zou, Zhou,Thomas, James B.,Brieaddy, Larry,Navarro, Hernán A.,Carroll, F. Ivy
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p. 1849 - 1860
(2008/09/21)
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- SAR studies of capsazepinoid bronchodilators. Part 1: The importance of the catechol moiety and aspects of the B-ring structure
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Capsazepine as well as its derivatives and analogues are general inhibitors of constriction of human small airways. From a systematic variation of the capsazepine structure, divided into four regions, SARs were established. This part concerns the catechol moiety of the A-ring as well as the 2,3,4,5-tetrahydro-1H-2-azepine moiety (the B-ring) of capsazepine. It is revealed that a conformational constrain (as a fused ring) is important and that compounds with a six-membered B-ring (as a 1,2,3,4-tetrahydroisoquinoline) in general are more potent than the corresponding isoindoline, 2,3,4,5-tetrahydro-1H-2-benzazepine and 2,3,4,5-tetrahydro-1H-3-benzazepine derivatives.
- Dalence-Guzman, Maria F.,Berglund, Magnus,Skogvall, Staffan,Sterner, Olov
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p. 2499 - 2512
(2008/09/21)
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- Discovery of novel tetrahydroisoquinoline derivatives as potent and selective factor Xa inhibitors
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A series of novel 2,7-disubstituted tetrahydroisoquinoline derivatives were designed and synthesized. Among these derivatives, compounds 1 and 2 (JTV-803) exhibited potent inhibitory activity against FXa and good selectivity with respect to other serine proteases (thrombin, plasmin, and trypsin). In addition, compound 2 exhibited potent anti-FXa activity after intravenous and oral administration to cynomolgus monkey, and showed a dose-dependent antithrombotic effect in a rat model of venous thrombosis.
- Ueno, Hiroshi,Yokota, Katsuyuki,Hoshi, Jun-Ichi,Yasue, Katsutaka,Hayashi, Mikio,Uchida, Itsuo,Aisaka, Kazuo,Hase, Yasunori,Katoh, Susumu,Cho, Hidetsura
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p. 185 - 189
(2007/10/03)
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- Synthesis and structure-activity relationships of novel selective factor Xa inhibitors with a tetrahydroisoquinoline ring
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A series of novel 2,7-disubstituted tetrahydroisoquinoline derivatives were designed and synthesized. Among these derivatives, compounds 1 and 2 exhibited potent inhibitory activity against factor Xa (FXa) and good selectivity with respect to other serine
- Ueno, Hiroshi,Yokota, Katsuyuki,Hoshi, Jun-Ichi,Yasue, Katsutaka,Hayashi, Mikio,Hase, Yasunori,Uchida, Itsuo,Aisaka, Kazuo,Katoh, Susumu,Cho, Hidetsura
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p. 3586 - 3604
(2007/10/03)
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- AZACYCLIC COMPOUNDS AS INHIBITORS OF SENSORY NEURONE SPECIFIC CHANNELS
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Compounds of the formula (I), and pharmaceutically acceptable salts thereof, are found to be antagonists of SNS sodium channels. They are therefore useful as analgesic and neuroprotective agents wherein: X is -N- or -CH-; n is from 0 to 3.
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- 2-CYANOPYRROLOPYRIMIDINES AND PHARMACEUTICAL USES THEREOF
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The invention relates to pyrrolo pyrimidines of formula (I), wherein Y represents -(CH2)t-O- or -(CH2)r-S-, p is 1 or 2, r is 1, 2 or 3, t is 1, 2 or 3, or Y is -(CH2)j- or -CH=CH-, j is 1 or 2; p is 1 or 2, or Y is -(CH2)f-, f is 1 or 2, p is 1, and the further radicals and symbols have the meaning as defined herein; their preparation, their use as pharmaceuticals, pharmaceutical compositions containing them, the use of such a compound for the manufacture of a pharmaceutical preparation for the treatment of neuropathic pain and to a method for the treatment of such a disease in animals, especially in humans.
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Page/Page column 50
(2010/02/08)
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- Heterocyclic derivatives and their use as antithrombotic agents
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The present invention relates to antithrombotic compounds comprising the group Q, Q having formula (I), wherein the substructure (i) is a structure selected from (a, b and c), wherein X is O or S; X′ being independently CH or N; and m is 0, 1, 2 or 3; wherein the group Q is bound through an oxygen atom or an optionally substituted nitrogen or carbon atom, or a pharmaceutically acceptable salt thereof or a prodrug thereof. The compounds of the invention are therapeutically active and in particular are antithrombotic agents.
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- Studies towards the next generation of antidepressants. Part 1: Indolylcyclohexylamines as potent serotonin reuptake inhibitors
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A series of indolylcyclohexylamines possessing potent and selective serotonin reuptake inhibition is reported. The most interesting compounds proved to have subnanomolar 5-HT transporter activity, and exhibited moderate 5-HT1A affinity.
- Meagher, Kristin L,Mewshaw, Richard E,Evrard, Deborah A,Zhou, Ping,Smith, Deborah L,Scerni, Rosemary,Spangler, Taylor,Abulhawa, Susan,Shi, Xiaojie,Schechter, Lee E,Andree, Terrance H
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p. 1885 - 1888
(2007/10/03)
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- A synthesis of mono- and dimethoxy-1,2,3,4-tetrahydroisoquinolines via Pummerer reaction: Effects of methoxyl groups on intramolecular cyclization
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A synthesis of 1,2,3,4-tetrahydroisoquinolines (TIQs) (23) with one and two methoxyl groups at various positions of the benzene ring was achieved via the intramolecular cyclization of N-(aryl)methyl-2- (phenylsulfinyl)ethylamines (9) using the Pummerer reaction as a key step. The reaction was carried out by using trifluoroacetic anhydride (TFAA) (method A) or TFAA-BF3 · Et2O (method B). The cyclization to 4-SPhTIQs (11) proceeded effectively when the reaction center at the benzene ring was electronically activated by a methoxyl group. In the reaction of the sulfoxide (9e) having two OMe groups at ortho- and para-positions a different cyclization reaction leading to a benzothiazepine (12) was observed, indicating that the high nucleophilicity of the benzene ring caused the unexpected reaction prior to the cyclization to 4-SPhTIQ (11e). The route starting from methoxylated benzaldehydes (5) was proved to provide an efficient and convenient method of TIQ synthesis which should be complementary to the well known Pictet-Spengler method.
- Shinohara, Tatsumi,Takeda, Akira,Toda, Jun,Ueda, Yoko,Kohno, Michiyo,Sano, Takehiro
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p. 918 - 927
(2007/10/03)
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- Inhibition of Complex I by Isoquinoline Derivatives Structurally Related to 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP)
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Mitochondrial respiratory failure secondary to complex I inhibition may contribute to the neurodegenerative process underlying nigral cell death in Parkinson's disease (PD). Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) may be inhibitors of complex I, and have been implicated in the cause of PD as endogenous neurotoxins. To determine the potency and structural requirements of isoquinoline derivatives to inhibit mitochondrial function, we examined the effects of 22 neutral and quaternary compounds from three classes of isoquinoline derivatives (11 isoquinolines, 2 dihydroisoquinolines, and 9 1,2,3,4-tetrahydroisoquinolines) and MPP+ on the enzymes of the respiratory chain in mitochondrial fragments from rat forebrain. With the exception of norsalsolinol and N,n-propylisoquinolinium, all compounds inhibited complex I in a time-independent, but concentration-dependent manner, with IC50s ranging from 0.36-22 mM. Several isoquinoline derivatives were more potent inhibitors of complex I than 1-methyl-4-phenylpyridinium ion (MPP+) (IC50 = 4.1 mM), the most active being N-methyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline (IC50 = 0.36 mM) and 6-methoxy-1,2,3,4-tetrahydroisoquinoline (IC50 = 0.38 mM). 1,2,3,4-Tetrahydroisoquinoline was the least potent complex I inhibitor (IC50 ca. 22 mM). At 10 mM, only isoquinoline (23.1 percent), 6,7-dimethoxyisoquinoline (89.6 percent), and N-methylsalsolinol (34.8 percent) inhibited (P +, so respiratory inhibition may underlie their reported neurotoxicity.
- Mcnaught, Kevin St. P.,Thull, Ulrike,Carrupt, Pierre-Alain,Altomare, Cosimo,Cellamare, Saverio,Carotti, Angelo,Testa, Bernard,Jenner, Peter,Marsden, C. David
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p. 1903 - 1912
(2007/10/03)
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- Inhibition of phenylethanolamine n-methyltransferase (PNMT) by aromatic hydroxy-substituted 1,2,3,4-tetrahydroisoquinolines: Further studies on the hydrophilic pocket of the aromatic ring binding region of the active site
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In a continuation of studies directed toward characterizing the hydrophilic pocket within the aromatic ring binding region of the active site of phenylethanolamine N-methyltransferase (PNMT), 5-, 6-, 7-, and 8-hydroxy-1,2,3,4-tetrahydroisoquinoline were prepared and evaluated as substates and inhibitors of PNMT. In order to discern the necessity of an acidic hydrogen for interaction at this pocket the corresponding methyl ethers were also evaluated. The enhanced affinity of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline (16) versus tetrahydroisoquinoline (13) itself indicates that a hydrophilic pocket exists off of carbon C7 in bound tetrahydroisoquinolines. The diminished affinity of the corresponding methyl ether is consistent with a requirement for the acidic hydrogen of 16 for interaction of the aromatic hydroxyl at site. From the relative activities of the other regioisomeric aromatic hydroxyl-substituted tetrahydroisoquinolines, their corresponding methyl ethers, and 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, it appears that the hydrophilic pocket is spatially compact with respect to bound tetrahydroisoquinolines and is surrounded by larger areas of lipophilic character. To allow a comparison of the results of this study with previous data on bound β-phenylethylamines, the methyl ethers of 5-, 6-, 7-, and 8-hydroxy-exo-2-aminobenzonorbornene and of 5- and 6-hydroxy-anti-9-aminobenzonorbornene were also evaluated for their activity as substrates and inhibitors for PNMT. The results of this study are in agreement with previous findings for bound β-phenylethylamines and support the conclusion that the natural substrate for PNMT, norepinephrine, has a different active site binding orientation than most known substrates and competitive inhibitors of the enzyme.
- Sall,Grunewald
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p. 2208 - 2216
(2007/10/02)
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- Synthesis of Fused Heterocycles: 1,2,3,4-Tetrahydroisoquinolines and Ring Homologues via Sulphonamidomethylation
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The title heterocycles (3) have been obtained by a two-step synthesis; namely an initial intramolecular sulphonamidomethylation of N-aralkylsulphonamides (1) in acid media followed by desulphonylation of compounds (2) under moderate conditions, either by reduction or acid hydrolysis.Generally both steps gave good or high yields of compounds (3) variously substituted in the aromatic ring and with a six-, seven-, or eight-membered heterocyclic ring.
- Orazi, Orfeo O.,Corral, Renee A.,Giaccio, Hector
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p. 1977 - 1982
(2007/10/02)
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- The Preparation and Oxidative Dimerisation of 2-Acetyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline. A New Approach to Tetrahydroisoquinoline Synthesis
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The title compound has been prepared from 1,2,3,4-tetrahydroisoquinoline via successive nitration, acetylation, reduction and diazotisation.Earlier conflicting reports on the nitration of tetrahydroisoquinoline have been clarified.A better synthetic route
- Ajao, J. F.,Bird, C. W.
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p. 329 - 331
(2007/10/02)
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- Compound 48/80. Structure activity relations and poly THIQ, a new, more potent analog
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Derivatives of p methoxyphenethylmethylamine were synthesized from which formaldehyde copolymers analogous to compound 48/80 were prepared. Measurement of the hypotensive activity of these analogs revealed that potency was not enhanced by changing the group in the para position, by varying the length of the alkyl group, or by altering the degree of methylation of the amine. However, when the ethylamine side chain was cyclized to form 7 methoxytetrahydroisoquinoline, the copolymer prepared from this derivative (poly THIQ) was seven times more potent than compound 48/80. The hypotensive action of poly THIQ was found to result from the liberation of histamine, as with compound 48/80.
- Read,Kiefer,Weber
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p. 1292 - 1295
(2007/10/04)
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