Syntheses and antitumor targeting G1 phase of the cell cycle of benzoyldihydroisoquinolines and related 1-substituted isoquinolines

A series of 1-substituted 3,4-dihydroisoquinolines were synthesized and tested in vitro against the leukemia L 1210 cell line to evaluate their ability to perturb the cell cycle by arresting cells in the G1 phase. 1-Benzoylimines, 1-phenylimines, and 1-alkylimines were synthesized. The most powerful cytotoxic derivatives, 1-benzoyl-3,4-dihydroisoquinolines (1-26), were obtained from amides I via 1-benzyl-3,4-dihydroisoquinoline in good yield by a direct selective oxidation of the benzylic carbon of the corresponding imines through 10% Pd/C in acetonitrile. SAR studies let us to identify the essential structural features for cytotoxic activity. The most bioactive compounds (with IC(50) < 5 microM) were BzDHIQ (13, 22, 21, 8, 9, 11, 1, 20, 6, and 19), and they are characterized by the following: (i) An alpha-ketoimine moiety is necessary for potent antiproliferative activity (1-phenyl- and 1-alkyl-3,4-dihydroisoquinoline derivatives, 34-40, are less active). (ii) An hydrophobic, benzyloxy, alkyloxy, or allyloxy group at the C-6 position seems to be relevant for cytotoxicity. (iii) Regarding the influence of the benzoylic moiety, both the unsubstituted (13, 8, 9, 11, 1, and 6) and the 3'-monosubstituted (22, 21, 20, and 19) compounds were more potent than compounds with other substitutions.     

Synthesis of 1-aroylmethyl-and 1-aryloxymethyl-3,4-dihydroisoquinolines and their effects on blood clotting

Acylation of a number of tertiary enamines with aroylchlorides was used to synthesize 1-aroylmethyl-3,4-dihydroisoquinolines. Reaction of 1-chloromethyl-3,3-dimethyl-3,4-dihydroisoquinoline with phenols with interphase catalysis was also used to make 1-aryloxymethyl-3,4-dihydroisoquinoline derivatives. 1-Aroylmethylisoquinolines characteristically had a hemostatic effect, while 1-aryloxymethyl-3,4-dihydroisoquinolines had an anticoagulant effect. The most active compound increased blood clotting by 17.7%. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 42, No. 2, pp. 18–20, February, 2008.     

Synthesis and antiinflammatory and analgesic activity of amidines of 3,4-dihydroisoquinoline series

A series of substituted 1-arylamino-3,4-dihydroisoquinolines have been synthesized using reactions of 1-methylthio-3,3-dimethyl-3,4-dihydroisoquinolines with substituted anilines and 2-aminothiazoles. The products were tested for analgesic and antiinflammatory activity. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 10, pp. 27–29, October, 2005.     

Synthesis,analgesic and anti-inflammatory activity of (1Z,3Z)-4-aryl-4-hydroxy-1-(3,3-dialkyl-3,4-dihydroisoquinoline-1(2H)-ylidene)-but-3-en-4-ones

It is established that 6-aryl-2,2-dimethyl-4H-1,3-dioxin-4-ones react with 3,3-dialkyl-1-methyl-3,4-dihydroisoquinolines with the formation of (1Z,3Z)-4-aryl-4-hydroxy-1-(3,3-dialkyl-3,4-dihydroisoquinoline1(2H)-ylidene)-but-3-en-4-ones. The synthesized compounds were tested for anti-inflammatory and analgesic properties.     

Synthesis of benzimidazole derivatives as potential antimicrobial agents

Three novel series of benzimidazol derivatives were prepared. Namely; 2-alkyl-1-(4-substituted-4H-1,2,4-triazole-5-thion-3-yl)methylb enzimidazoles; 2-alkyl-1-(5-substituted amino-1,3,4-thiadiazol-2-yl)methylbenzimidazoles; and 2-alkyl-1-[(3,4-disubstituted thiazolin-2-ylidene)hydrazinocarbonyl] methylbenzimidazoles. The antimicrobial testing of the prepared compounds as well as of the key intermediate thiosemicarbazides was performed.     

Antiarrhythmic,Hemostatic, Anthelmintic,and Larvicidal Activity of 3,3-Dialkyl-Substituted Drotaverine Analogs

Pharmaceutical Chemistry Journal - Previously obtained hydrochlorides of 1-[3,4-(R1)2-benzyl]-3,3-(R2)2-6,7-(R3)2-3,4-dihydroisoquinolines (R1 = H, MeO, EtO; R2 = Alk; R3 = MeO, EtO) and their...     

Synthesis and Antiinflammatory and Analgesic Activity of 2H-3,3-Dimethyl-3,4-dihydroisoquinolin-1-ones

The reactions of substituted arenes with isobutyric aldehyde and methylthiocyanate yield 1-methylthio-3,4-dihydroisoquinolines. The subsequent treatment with AcOH/AcONa yields 2H-3,3-dimethyl-3,4-dihydroisoquinolin-1-ones, some of which exhibit pronounced antiinflammatory and analgesic properties. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 8, pp. 13 – 15, August, 2005.     

Untersuchungen zur Reaktion cyclischer Imine mit Chinonmethiden

Investigations about the Reaction of Cyclic Imines with Quinone Methids Alkyl substituted Δ1-pyrrolines, 3H-indoles or 3,4-dihydroisoquinolines do not react with quinone methids to yield Diels-Alder adducts. Instead, the reactions afford by C-alkylation the hydroxybenzyl derivatives 2, 4, 5 and 9–12 . This constitutes a general approach to hydroxybenzyl derivatives of CH-acidic cyclic imines and is of interest in the synthesis of β-phenylethyl-1,2,3,4-tetrahydroisoquinolines.     

Synthesis and analgesic and anti-inflammatory activities of (2Z,5Z)-1-aryl-3-hydroxy-5-(3,3-dialkyl-3,4-dihydroisoquinolin-1(2<Emphasis Type="Italic">H</Emphasis>)-yliden)pent-2-en-1,4-diones

5-Arylfuran-2,3-diones and (Z)-alkyl-4-aryl-2-hydroxy-4-oxobut-2-enoates react with 3,3-dialkyl-1-methyl-3,4-dihydroxyisoquinolines to form (2Z,5Z)-1-aryl-3-hydroxy-5-(3,3-dialkyl-3,4-dihydroxyisoquinolin-1(2H)-yliden)pent-2-en-1,4-diones which have analgesic and anti-inflammatory activities.     

Synthese und Eigenschaften von 4-Alkyl-2-phenyl-3,4-dihydro-5H-1,4-benzodiazepin-5-onen

Synthesis and Reactions of 4-Alkyl-2-phenyl-3,4-dihydro-5H-1,4-benzodiazepine-5-ones The synthesis of the 4-alkyl-2-phenyl-3,4-dihydro-5H-1,4-benzodiazepine-5-ones (1a) by reductive cyclisation of the corresponding 2-nitro-N-alkyl-N-phenacylbenzamides (5) is reported. The different reactions of the new 4-alkyl-derivatives and the known 4-unsubstituted compounds of this ring system are described.     

Derivatives of the 1,2,3,4,5-pentahydro-2-benzazepine

Derivatives of 1,2,3,4,5-Pentahydro-2-benzazepine By treating 3,4,10,11-dibenzo-1,8-diaza cyclotetradeca-1,3,8, 10-tetraene (3) with methyl or ethyl iodide in ethanol 2-alkyl-3,4-dihydro-5H-2-benzazepinium iodides 4 are formed. With potassium cyanide in aqueous solution they are converted to N-alkyl-1-cyan-1,2,3,4,5-pentahydro2-benzazepines 5 . Lithium aluminium hydride reduction of compounds 5 leads to 2-alkyl-1-aminomethyl-1,2,3,4,5-pentahydro-2-benzazepines 6 .     

Synthesis and anticoagulant activity of 1-aryl derivatives of tetrahydroisoquinolines

A series of 1-aryl-3,3-dimethyl-3,4-dihydroisoquinolines were obtained by three-component (one-pot) condensation of veratrole, isobutylene oxide, and aromatic nitriles and then reduced to the corresponding 1,2,3,4-tetrahydroisoquinolines. Hydrochlorides of the synthesized compounds were tested for anticoagulant activity. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 7, pp. 18–20, July, 2006.     

Zur Kondensation von Iminopentenaminen mit (1-Chloralkyliden)-propandinitrilen

Condensation of Iminopentenamines with (1-Chloroalkylidene)propanedinitriles Condensation of N-alkyl-4-alkylimino-2-penten-2-amines 1 with (1-chloroalkylidene)propanedinitriles 2 leads to the 2-imino-1,2-dihydropyridine-3-carbonitriles 4 , which exist in solution as E/Z-mixtures. With perchloric acid 4a yields the diperchlorate 6 . Monomethylation of 4a followed by deprotonation gives rise to 7 , bismethylation and deprotonation leads to 9 . In the reaction of 1 with chloroethene-tricarbonitrile ( 10 ) the tetrahydropyrrolo[3,4-c]pyridine-7-carbonitriles 12 are formed.     

CoMFA on the melanogenesis inhibitory activity of alkyl-3,4-dihydroxybenzoate, N-alkyl-3,4-dihydroxybenzamide analogues, and prediction of higher active compounds

To predict a new materials of superior melanogenesis inhibitory activities (MIA), the comparative molecular field analysis (CoMFA) models on MIA of alkyl-3,4-dihydroxybenzoates and N-alkyl-3,4-dihydroxybenzamides analogues against mouse melanoma cell were derived and discussed quantitatively. The optimized CoMFA model II from the field fit alignment demonstrated better predictability of molecular structure with the non-cross validated conventional coefficient (r² _nev.=0.984) and cross-validated coefficient (r² _cv. or q=0.706) than that from atom based fit alignment. Also, the relative contribution of the optimized CoMFA model II showed the steric (63.8%), electrostatic (18.4%), and hydrophobic (ClogP) field (17.8%), respectively. The results indicated that the esters (alkyl-3,4-dihydroxybenzoates) are more active inhibitors than the amides (N-alkyl-3,4-dihydroxybenzamides). Furthermore, the optimized CoMFA model II is proven to be a useful approach to design a highly active melanogenesis inhibitor molecules, and enables to predict R₁=n-dodecy and R₂=n-heptyloxy substituted compound of alkyl-3,4-dihydroxybenzoates as the most active compounds (Pred. pI₅₀=5.87).     

Zum Mechanismus der Bischler-Napieralski-Reaktion, 2. Mitt. o-Chlorierte β-Phenethylcarbonsäureamide als Nebenprodukte beim Ringschluß mit PCl5

The Mechanism of the Bischler-Napieralski Reaction, II: o-Chlorinated β-Phenethylamides as By-Products of the Ring Closure with PCl₅ In addition to 3,4-dihydroisoquinolines o-chloro-β-phenethylamides are formed in the Bischler-Napieralski reaction using PCl₅. Possible mechanisms for the chlorination were tested in model experiments.     

Synthese und Reaktionsverhalten 4-phenylsubstituierter Isochinuclidine

Synthesis and Reactivity of 4-Phenylisoquinuclidines Several approaches to the synthesis of the 2-alkyl-4-phenylisoquinuclidines 14 and 15 , the 3,4-diphenylisoquinuclidines 22–24 and of 6-oxo-4-phenyl-3-isoquinuclidone (43) are described. The structures of the products of hydrolysis of 7-phenyl-1,4-dioxaspiro[4.5]decanecarboxamide (36) were determined by spectroscopy and degradative reactions.     

Dihydroisochinolinumlagerung, 32. Mitt.1) 4-Benzyl-5-methyl-4,5-dihydrothieno[3,2-c]pyridine

Dihydroisoquinoline Rearrangement, XXXII: 4-Benzyl-5-methyl-4,5-dihydrothieno[3,2-c]pyridines The synthesis of the title compounds 4a–4c was performed via the 4-benzylthieno[3,2-c]pyridines 2a–2c which were obtained by Grignard coupling or by Wittig alkylation of the chlorothienopyridine 1. Compounds 2a–2c were N-methylated to yield 3a–3c which in turn were reduced with LiAlH₄ to give the 4,5-dihydrothieno[3,2-c]pyridines 4a–4c. On treatment of 4a and 4b with dilute acids the disproportionation products 3a, 9a , and 3b, 9b were obtained with 10% yield. Treatment of 4c with dilute acid gave the disproportionation products 3c and 9c as well as the rearrangement product 8c with 30% yield. This shows that compounds other than 1,2-dihydroisoquinolines can rearrange in the same way as 1-benzyl-1,2-dihydroisoquinolines.     

Stereoselective synthesis of cyclopentanones using dirhodium(II)-catalyzed intramolecular C-H insertion reaction

This review summarizes novel stereoselective syntheses of 3,4-cis- and 3,4-trans-3-alkyl-4-silyloxycyclopentanones using a dirhodium(II)-catalyzed intramolecular C-H insertion reaction as a key reaction. Treatment of diazoketoesters (20a-e) with 1 mol % of dirhodium(II) tetraacetate gave 2,3-trans-3,4-cis-cyclopentanones (21a-e) as major products. The presence of both the keto and ester groups in the precursors was found to be essential for this chemo- and stereoselective intramolecular C-H insertion reaction to take place. A possible interpretation for the observed stereoselectivity is presented. Optically active Corey lactone (38) was synthesized using a similar reaction of chiral alpha-diazo-beta-ketoester (33). Next, reactions of 5,6-bisoxygenated diazoketones with Rh2(OAc)4 were investigated. An acetonide derivative (39), upon treatment with Rh2(OAc)4, gave 3,8-dioxabicyclo[3.2.1]octane (42) via oxonium ylide formation/1,2-shift. On the other hand, similar treatment of 5,6-bis(tert-butyldimethylsilyloxy) derivative (47) gave a C-H insertion product (51) which was purified by silica gel column chromatography to give 4-silyloxycyclopentenone (48). Direct reduction of 51 with lithium aluminum hydride gave stereoselectively diol (52) in 52% yield from 47. Reaction of 2-methoxycarbonylcyclopentenone (48) and a 2-benzenesulfonyl congener (50) with R2CuLi or RMgBr-CuI stereoselectively gave 2,3-trans-3,4-trans-cyclopentanones (22, 57) as a major diastereoisomer. On the other hand, reaction with R3 Al in toluene exclusively gave the corresponding 3,4-cis-adducts (21 and 58).     

Synthesis and Antimicrobial Activity of Some Pyrrolo[1,2,3-de]-1,4-benzothiazines,Part 2

Acid catalyzed cyclization reactions of both 3-alkyl- and 3-aryl-substituted N-/2,2-dialkoxyethyl)-3,4-dihydro-2H-1,4-benzothiazines ( 2 ) lead to 2,3-dihydro-pyrrolo[1,2,3-de]-1,4-benzothiazines ( 3 ). The pyrrolobenzothiazine structure was deduced on the basis of 2D ¹H NMR-NOESY experiments and fully determined by X-ray data. Compounds 3a-c showed poor antibacterial activity. However, the 3-phenyl-N-(2,2-dimethoxyethyl)-3,4-dihydro-2H-1,4-benzothiazine ( 2b′ ) showed antifungal activity against Aspergillus niger 16-fold greater than miconazole.     

Solution-phase parallel synthesis of a diverse library of 1,2-dihydroisoquinolines

Synthesis of a 105 membered library of 1,2-dihydroisoquinolines is described. The 1,2-dihydroisoquinoline compounds have been prepared in good yields using a Lewis acid and organocatalyst-cocatalyzed multicomponent reaction of 2-(1-alkynyl)benzaldehydes, amines, and ketones. Various indoles have also been employed as pronucleophiles, furnishing 1-(3-indolyl)-1,2-dihydroisoquinolines. The halogen functionality present in some of the synthesized compounds allows for further diversification by palladium-catalyzed Suzuki?Miyaura and Sonogashira cross-couplings to give more diversified 1,2-dihydroisoquinoline derivatives.