- A xylochemically inspired synthesis of lamellarin G trimethyl ether via an enaminone intermediate
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A concise high yielding synthesis of lamellarin G trimethyl ether has been achieved from precursors and solvents that can in principle be derived from xylochemical (woody biomass) sources. The route is comparatively green in that some reactions are performed without solvent or with relatively benign solvents. In addition, chromatographic purification of products is avoided, and only a single aqueous workup is performed. The novelty of the synthesis lies in the intermediacy of an enaminone for the construction of the central pyrrole ring. The overall yield of the product is among the highest reported to date.
- Klintworth, Robin,De Koning, Charles B.,Opatz, Till,Michael, Joseph P.
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Read Online
- Carbon-13 NMR Spectra of Tembamide, Aegeline and Related Amides
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Carbon-13 NMR spectral studies of tembamide (1) and aegeline (2), constituents of Fagara hyemalis and Aegle marmelos respectively, and a series of their structurally related amides (3-13) have been carried out.The assignment of the resonances of two related dimers are also reported.The assignment of the various resonances were made by considering the changes in chemical shifts produced by the change of substituents and also by using 1, 13 and a related compound as model compounds.
- Patra, Amarendra,Mitra, Alok K.,Ghosh, Arundhati,Mukhopadhyay, Prabir K.
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Read Online
- COMPOUNDS, COMPOSITIONS AND METHODS FOR TREATING NASH, NAFLD, AND OBESITY
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The present technology relates to methods of treating NASH, NAFLD and/or obesity using compounds of Formulas I, II, III, IV, V, and/or VI. The methods include administering to a subject suffering from one or more of non-alcoholic steatohepatitis (NASH), non- alcoholic fatty liver disease (NAFLD) and/or obesity a therapeutically effective amount of such a compound
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Paragraph 00245
(2021/04/10)
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- Preparation method of papaverine
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The invention discloses a preparation method of papaverine. The invention provides a preparation method of papaverine, which comprises the following steps: (1) in a solvent, in the presence of a cyclization agent, carrying out cyclization reaction as shown in the specification on a compound as shown in a formula I to obtain a compound as shown in a formula II; and (2) in a solvent, in the presence of a dehydrogenation catalyst, carrying out dehydrogenation reaction as shown in the specification on the compound as shown in the formula II to obtain papaverine. The compound as shown in the formula II prepared in the step (1) is directly used in the step (2) without being purified. The method is simple in process, easy to operate, low in cost and suitable for industrial production, and the product is high in yield and purity.
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Paragraph 0071-0072; 0080-0111
(2021/06/09)
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- Synthesis and SARs of dopamine derivatives as potential inhibitors of influenza virus PAN endonuclease
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Currently, influenza PAN endonuclease has become an attractive target for development of new drugs to treat influenza infections. Herein we report the discovery of new PAN endonuclease inhibitors derived from a chelating agent dopamine moiety. A series of dopamine amide derivatives and their conformationally constrained 1,2,3,4-tetrahydroisoquinoline-6,7-diol-based analogs were elaborated and assayed against influenza virus A/WSN/33 (H1N1). Most compounds exhibited moderate to excellent antiviral activities, generating a preliminary SARs. Among them, compounds 14 and 19 showed stronger anti-IAV activity compared with the reference Peramivir. Moreover, 14 and 19 demonstrated a concentration-dependent inhibition of PAN endonuclease based on both FRET assay and SPR assay. Docking studies were also performed to elucidate the binding mode of 14 and 19 with the PAN protein and to identify amino acids involved in their mechanism of action, which were well consistent with the biological data. This finding was beneficial to laying the foundation for the rational development of more effective PAN endonuclease inhibitors.
- Liao, Yixian,Ye, Yilu,Li, Sumei,Zhuang, Yilian,Chen, Liye,Chen, Jianxin,Cui, Zining,Huo, Lijian,Liu, Shuwen,Song, Gaopeng
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- One-Pot Synthesis of Papaverine Hydrochloride and Identification of Impurities
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Abstract: A one-pot synthesis of papaverine hydrochloride with 99.6% purity was performed using xylene as solvent for the entire process. The critical parameters of each step, as well as the impurities generated, were identified. The overall yield was improved to 63%. The proposed synthetic procedure is suitable for industrial production.
- Qiu, Zeng-Feng,Wu, Ze-Nong,Yang, Zhe-Zhou,Yu, Wen-Shuai,Zhang, Fu-Li,Zhao, Chun-Jie
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p. 1295 - 1299
(2020/09/16)
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- Preparation of powder injection pharmaceutical composition from high-purity papaverine hydrochloride
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The invention relates to preparation of a powder injection pharmaceutical composition from high-purity papaverine hydrochloride, in particular to a preparation method of papaverine hydrochloride. Themethod comprises the following steps of: heating 3, 4-dimethoxy-beta-phenyl-ethylamine and 3, 4-dimethoxy-phenyl-acetic acid to melting, and then carrying out reaction in a mixture of benzene and chlorethoxyfos to obtain 6, 7, 3', 4'-tetramethoxy-1-benzyl-dihydro-isoquinoline hydrochloride; then dissolving the wet product in tetrahydronaphthalene after the wet product becomes free alkali, and carrying out dehydrogenation reaction at 180DEG C in the presence of a Raney nickel catalyst; after dehydrogenation is finished, directly filtering the tetrahydronaphthalene reaction mixture from the Raney nickel catalyst into a mixture of a hydrochloric acid aqueous solution and methanol; filtering out precipitates, and performing recrystallizing from the ethanol-water solution in an inert gas environment to obtain off-white 6, 7, 3', 4'-tetramethoxy-1-benzyl isoquinoline hydrochloride, namely papaverine hydrochloride. The invention also relates to a papaverine hydrochloride powder injection pharmaceutical composition, and a preparation method and a quality detection method thereof. The invention achieves excellent technical effects as described in the specification.
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Paragraph 0251; 0252; 0255; 0256; 0259; 0260
(2020/11/12)
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- Oxidative route to pyrroloisoquinoline-2,3-dione
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We herein report an efficient constructive method for synthesis of structurally important Pyrroloisoquinoline-2,3-dione from dihydroisoquinoline through oxidative cyclisation. Process is optimised to give best efficiency at gram scale and laborious purification techniques such as column chromatography or recrystallisation were avoided in all steps further featuring uniqueness of this method as compared to the available literature.
- Kadam, Hari K.,Tilve, Santosh G.
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p. 184 - 190
(2018/06/15)
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- Application of differential reactivity towards synthesis of lamellarin and 8-oxoprotoberberine derivatives: Study of photochemical properties of aryl-substituted benzofuran-8-oxoprotoberberines
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A unique differential reactivity between dihydroisoquinolines and 3-nitrocoumarins was observed and was exploited for the efficient construction of lamellarins and their isomeric benzofuran-8-oxoprotoberberine derivatives under acid-catalyzed or base-promoted conditions. Further, these prepared aryl-substituted benzofuran-8-oxoprotoberberine derivatives bearing electron-donating substituents on benzofuran moiety are found to be benchtop stable but light-sensitive, and can undergo oxidative ring-opening reaction to give the corresponding keto products when exposed to visible light under aerobic conditions.
- Vyasamudri, Sameer,Yang, Ding-Yah
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supporting information
p. 1092 - 1100
(2018/02/06)
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- A facile synthesis of 1-oxo-pyrrolo[2,1-a]isoquinolines
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The facile synthesis of 1-oxo-pyrrolo[2,1-a]isoquinolines from the reaction of 1-aroyl-3,4-dihydroisoquinolines and symmetrical alkynes in toluene is described. The novel compounds contain functional groups that are suitable for further modification.
- Voskressensky, Leonid G.,Borisova, Tatiana N.,Matveeva, Maria D.,Khrustalev, Viktor N.,Titov, Alexander A.,Aksenov, Alexander V.,Dyachenko, Svetlana V.,Varlamov, Alexey V.
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supporting information
p. 877 - 879
(2017/02/18)
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- Domino Reactions of 1-Aroyl-3,4-dihydroisoquinolines with α,β-Unsaturated Aldehydes
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An efficient synthesis of pyrrolo[2,1- a ]isoquinolines by a domino reaction from a variety of 3,4-dihydropyrrolo[2,1- a ]isoquinolines and α,β-unsaturated aldehydes in the absence of catalyst in good yields under microwave irradiation, is reported.
- Matveeva, Maria D.,Borisova, Tatiana N.,Titov, Alexander A.,Anikina, Lada V.,Dyachenko, Svetlana V.,Astakhov, Grigorii S.,Varlamov, Alexey V.,Voskressensky, Leonid G.
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supporting information
p. 5251 - 5257
(2017/10/06)
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- Effect of 1-Substitution on Tetrahydroisoquinolines as Selective Antagonists for the Orexin-1 Receptor
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Selective blockade of the orexin-1 receptor (OX1) has been suggested as a potential approach to drug addiction therapy because of its role in modulating the brain's reward system. We have recently reported a series of tetrahydroisoquinoline-based OX1 selective antagonists. Aimed at elucidating structure-activity relationship requirements in other regions of the molecule and further enhancing OX1 potency and selectivity, we have designed and synthesized a series of analogues bearing a variety of substituents at the 1-position of the tetrahydroisoquinoline. The results show that an optimally substituted benzyl group is required for activity at the OX1 receptor. Several compounds with improved potency and/or selectivity have been identified. When combined with structural modifications that were previously found to improve selectivity, we have identified compound 73 (RTIOX-251) with an apparent dissociation constant (Ke) of 16.1 nM at the OX1 receptor and >620-fold selectivity over the OX2 receptor. In vivo, compound 73 was shown to block the development of locomotor sensitization to cocaine in rats. (Chemical Equation Presented).
- Perrey, David A.,German, Nadezhda A.,Decker, Ann M.,Thorn, David,Li, Jun-Xu,Gilmour, Brian P.,Thomas, Brian F.,Harris, Danni L.,Runyon, Scott P.,Zhang, Yanan
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p. 599 - 614
(2015/04/27)
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- Efficient and Practical Syntheses of Enantiomerically Pure (S)-(-)-Norcryptostyline I, (S)-(-)-Norcryptostyline II, (R)-(+)-Salsolidine and (S)-(-)-Norlaudanosine via a Resolution-Racemization Method
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Four racemic tetrahydroisoquinolines (RS)-(±)-1-4 were prepared from homoveratrylamine via amidation, Bischler-Napieralski reaction and the subsequent reduction. The enantiomerically pure tetrahydroisoquinolines (S)- (-)-norcryptostyline I [(S)-(-)-1], (S)-(-)-norcryptostyline II [(S)-(-)-2], (R)-(+)-salsolidine [(R)-(+)-3] and (S)-(-)-norlaudanosine [(S)-(-)-4] were then obtained in 45%, 40%, 41% and 38% yields, respectively, via resolution of the racemic compounds (RS)-(±)-1-4 with half equivalent of chiral acids. In addition, the enantiomerically enriched compounds (R)-(+)-1, (R)-(+)-2, (S)-(-)-3 and (R)-(+)-4 from the mother liquors were efficiently racemized via a one-pot redox method in almost quantitative yields.
- Zhu, Ruiheng,Xu, Zhangli,Ding, Wei,Liu, Shiling,Shi, Xiaoxin,Lu, Xia
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p. 1039 - 1048
(2016/02/18)
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- Total synthesis of 8-epi-javaberine A and javaberine A
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The total synthesis of berberine alkaloid javaberine A was examined. The B/C ring of berberine was successfully constructed by sequential Bischler-Napieralski cyclization-reduction protocols, and final demethylation afforded both javaberine A and its epimer.
- Yamamoto, Yasutomo,Tabuchi, Yuri,Baba, Ayana,Hideshima, Kumiko,Nakano, Mai,Miyawaki, Akari,Tomioka, Kiyoshi
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p. 1311 - 1321
(2016/11/07)
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- Toward the development of bivalent ligand probes of cannabinoid CB1 and Orexin OX1 receptor heterodimers
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Cannabinoid CB1 and orexin OX1 receptors have been suggested to form heterodimers and oligomers. Aimed at studying these complexes, a series of bivalent CB1 and OX1 ligands combining SR141716 and ACT-078573 pharmacophores were designed, synthesized, and tested for activity against CB1 and OX1 individually and in cell lines that coexpress both receptors. Compound 20 showed a robust enhancement in potency at both receptors when coexpressed as compared to individually expressed, suggesting possible interaction with CB1-OX1 dimers. Bivalent ligands targeting CB1-OX1 receptor dimers could be potentially useful as a tool for further exploring the roles of such heterodimers in vitro and in vivo.
- Perrey, David A.,Gilmour, Brian P.,Thomas, Brian F.,Zhang, Yanan
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p. 634 - 638
(2014/07/07)
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- Acceptorless dehydrogenation of nitrogen heterocycles with a versatile iridium catalyst
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Gas up: A cyclometalated iridium complex is found to catalyze the dehydrogenation of various benzofused N-heterocycles, thus releasing H 2. Driven by as low as 0.1 mol % catalyst, the reaction affords quinolines, indoles, quinoxalines, isoquinolines, and β-carbolines in high yields. Copyright
- Wu, Jianjun,Talwar, Dinesh,Johnston, Steven,Yan, Ming,Xiao, Jianliang
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supporting information
p. 6983 - 6987
(2013/07/26)
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- Restraining the flexibility of the central linker in terameprocol results in constrained analogs with improved growth inhibitory activity
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The semi-synthetic lignan terameprocol inhibits the transcription of several inflammatory and oncogenic genes and has been evaluated for its anti-cancer properties. Here we investigated the effect of restricting the flexibility of the carbon linker connecting the terminal rings of terameprocol on its growth inhibitory activity. Conformational restriction was explored by introducing unsaturation, inserting polar entities with limited flexibility and cyclization of the connecting linker. Twenty three compounds were synthesized and evaluated on a panel of malignant human cells. The most promising compounds were those with non-polar linkers, as seen in butadiene 1a and the cyclized benzylideneindane analog 7. Both compounds were more potent than terameprocol on pancreatic BxPC-3 cells with GI50 values of 3.4 and 8.1 μM, respectively. Selected isomers of 1a (E,E) and 7 (Z) adopted low energy bent conformations that mimicked the low energy conformer of terameprocol. It is tempting to propose that conformational similarity to terameprocol may have contributed to their good activity. The scaffolds of 1a and 7 should be further investigated for their anticancer potential.
- Ho, Sherman Si Han,Go, Mei Lin
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supporting information
p. 6127 - 6133
(2013/11/06)
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- Discovery and Characterization of ACT-335827, an Orally Available, Brain Penetrant Orexin Receptor Type1 Selective Antagonist
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Stress relief: Orexin neuropeptides regulate arousal and stress processing through orexin receptor type1 (OXR-1) and 2 (OXR-2) signaling. A selective OXR-1 antagonist, represented by a phenylglycine-amide substituted tetrahydropapaverine derivative (ACT-335827), is described that is orally available, penetrates the brain, and decreases fear, compulsive behaviors and autonomic stress reactions in rats. Copyright
- Steiner, Michel A.,Gatfield, John,Brisbare-Roch, Catherine,Dietrich, Hendrik,Treiber, Alexander,Jenck, Francois,Boss, Christoph
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supporting information
p. 898 - 903
(2013/07/27)
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- 1,2,3,4-tetrahydroisoquinoline derivative and its use as orexin receptor antagonist
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The invention relates to the compound (R)-2-[(S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-isopropyl-2-phenyl-acetamide; and to its use as active ingredient in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compound, pharmaceutical compositions containing the compound and methods of treatment comprising administration of said compound to a human being.
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Page/Page column 10
(2012/02/04)
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- Synthesis and biological evaluation of a series of 6,7-dimethoxy-1-(3,4- dimethoxybenzyl)-2-substituted tetrahydroisoquinoline derivatives
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Multidrug resistance in cancer is a major cause of failure in cancer chemotherapy. In search of new compounds with strong reversal activity and simple molecular structure, we have synthesized a series of compounds in which different substituents were linked to the 2-position of the 6,7-dimethoxy-1-(3, 4-dimethoxybenzyl)-tetrahydroisoquinoline system. Compounds were analyzed for their cytotoxicity by MTT in K562 cell line in vitro, all of the derivatives exhibited little cytotoxic activity. In the meantime, these compounds were evaluated by MTT in K562/A02 cell line in vitro, 6e, 6h and 7c exhibited similar or more potent activities than verapamil with the IC50 values at 0.66, 0.65 and 0.96μM, and with the ratio factor of 24.13, 24.50 and 16.59, respectively.
- Zou, Zhi-Hong,Lan, Xiao-Bu,Tang, Chun-Lei,Zhu, Xiao-Yun,Liu, Bao-Min,Qian, Hai,Huang, Wen-Long,Li, Yun-Man
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scheme or table
p. 711 - 716
(2012/09/22)
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- Synthesis and evaluation of furoxan-based nitric oxide-releasing derivatives of tetrahydroisoquinoline as anticancer and multidrug resistance reversal agents
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Multidrug resistance in tumor cells poses a major obstacle to efficient chemotherapy. Several types of agents have been recognized as multidrug resistance inhibitors, among which the tetrahydroisoquinolines is the most studied. In current study 16 furoxan-based nitric oxide-releasing derivatives of tetrahydroisoquinoline were synthesized. Their cytotoxic activities and effects in reversing multidrug resistance have been evaluated. The results revealed that these compounds had moderate cytotoxic effects. Compounds 7a-f, 7h, and 7l showed higher cytotoxicities than the rest, but lower than adriamycin on K562 cell line. Compounds 7d, 7f, and 7l exhibited potent MDR reversal activities on K562/A02 cell line. The accumulation assay indicated that compounds 7d, 7f, and 7l significantly increased the intracellular accumulation of rhodamine123 in K562/A02 cells. Furthermore, these three compounds produced high concentrations of NO in K562/A02 cells. Potentially, the high concentrations of NO produced by NO donor moieties will lead to an increased cytotoxicity to K562/A02 cells. Our results suggested that compounds 7d, 7f, and 7l had anticancer effects, as well as multidrug resistance reversal effects.
- Zou, Zhi-Hong,Lan, Xiao-Bu,Qian, Hai,Huang, Wen-Long,Li, Yun-Man
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scheme or table
p. 5934 - 5938
(2011/10/09)
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- Novel hybrids from lamellarin D and combretastatin A 4 as cytotoxic agents
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A new series of hybrids of lamellarin D and combretastatin A 4, 1,2-diphenyl-5,6-dihydropyrrolo [2,1-a] isoquinolines, were designed as cytotoxic agents based on principles of combination in medicinal chemistry and taking the parent compounds' different anti-proliferative mechanisms into consideration. Twenty-two novel hybrids were synthesized through a convenient route, with a key step of core pyrrole formation and evaluated for their anti-proliferative activities in vitro against K-562, A-549, SMMC-7721, SGC-7901 and HCT-116 cancer cell lines. The results showed that some hybrids had good anti-proliferative activities in low IC50 ranges.
- Shen, Li,Yang, Xiaochun,Yang, Bo,He, Qiaojun,Hu, Yongzhou
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experimental part
p. 11 - 18
(2010/03/03)
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- CORYDALINE DERIVATIVES USEFUL FOR REDUCING LIPID LEVELS
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The present technology relates to compounds of Formulas (V) and (VI) and methods of making and using such compounds. Methods of use include prevention and treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, and metabolic syndrome. Compounds disclosed herein also lower total cholesterol, LDL- cholesterol, and triglycerides and increase hepatic LDL receptor expression, inhibit PCSK9 expression, and activate AMP-activated potein kinase.
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Page/Page column 88
(2010/07/09)
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- COMPOUNDS, COMPOSITIONS AND METHODS FOR REDUCING LIPID LEVELS
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Compositions comprising extracts or isolated or purified compounds from plants of the genus Corydalis provide prevention and treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, and metabolic syndrome. Corydalis compounds and their derivatives of natural and synthetic origins lower total cholesterol, LDL-cholesterol, and triglycerides and increase hepatic LDL receptor expression and activate AMP-activated protein kinase. Specific stereoisomers of Corydalis compounds with lipid lowering activity include 14R-(+)-corypalmine, 14R,13S-(+)-corydaline, 14R-(+)-tetrahydropalmatin, (+)-corlumidin, d-(+)-bicuculline, and (+)-egenine.
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Page/Page column 38
(2009/03/07)
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- Design and synthesis of tetrahydroisoquinoline derivatives as potential multidrug resistance reversal agents in cancer
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Exploration for new MDR-modulator utilizing tetrahydroisoquinoline as scaffold disclosed 6,7-dimethoxy-1-(3,4-dimethoxy)benzyl-2-(N-n-octyl-N′-cyano)guanyl-1,2,3,4-tetrahydroisoquinoline (7) as a readily accessible medicinal lead. Compound 7 possessed potent MDR reversal activity in the range of the reference compound verapamil, and had not cardiovascular activity compared to verapamil. Crown Copyright
- Li, Yu,Zhang, Hui-bin,Huang, Wen-long,Li, Yun-man
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body text
p. 3652 - 3655
(2009/04/10)
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- A variation of the Pictet-Spengler reaction via a sequential reduction-cyclization reaction of N-acylcarbamates: synthesis of 1-substituted tetrahydroisoquinoline derivatives
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A new variation of the Pictet-Spengler reaction for the synthesis of 1-substituted tetrahydroisoquinoline derivatives has been developed. The reaction employs the reduction of N-acylcarbamates by DIBAL-H followed by simultaneous cyclization mediated by BF3·OEt2. The synthetic potential of this method has been illustrated by the synthesis of the tetrahydroisoquinoline alkaloids, (±)-xylopinine, (±)-laudanosine, (±)-8-oxo-O-methylbharatamine, and (±)-isoindoloisoquinolone.
- Kuhakarn, Chutima,Panyachariwat, Nattakan,Ruchirawat, Somsak
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p. 8182 - 8184
(2008/03/14)
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- Total synthesis of natural and unnatural lamellarins with saturated and unsaturated D-rings
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(Chemical Equation Presented) Twenty-eight natural and unnatural lamellarins with either a saturated or an unsaturated D-ring were synthesized according to our developed synthetic route. The key step involved the Michael addition/ring closure (Mi-RC) of the benzyldihydroisoquinoline and α-nitrocinnamate derivatives, which provided the 2-carboethoxypyrrole intermediates in moderate to good yields (up to 78% yield). Subsequent hydrogenolysis/lactonization furnished lamellarins with a saturated D-ring in excellent yields (up to 93% yield). DDQ oxidation of the saturated lamellarin acetates led directly to the corresponding unsaturated analogues in 54-95% yield. In addition, only two steps in our developed strategy require column chromatography.
- Ploypradith, Poonsakdi,Petchmanee, Thaninee,Sahakitpichan, Poolsak,Litvinas, Nichole D.,Ruchirawat, Somsak
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p. 9440 - 9448
(2007/10/03)
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- Enantioselective synthesis of some tetracyclic isoquinoline alkaloids by asymmetric transfer hydrogenation catalysed by a chiral ruthenium complex
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Asymmetric transfer hydrogenation catalysed by chiral ruthenium complexes was the method for enantioselective synthesis of (R)-(+)-coralydine, (S)-(-)-homoprotoberberine, and (S)-(+)-homoaporphine in fair to excellent enantiomeric purity. Springer-Verlag 2005.
- Szawkalo, Joanna,Czarnocki, Zbigniew
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p. 1619 - 1627
(2007/10/03)
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- Synthesis and antispasmodic activity evaluation of bis-(papaverine) analogues
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A new series of N-substituted bis-(tetrahydropapaverine) ring systems have been synthesised in expectation of better antispasmodic activity in comparison with papaverine. The synthesis of the targeted heterocycles is described along with a discussion of their structure activity relationship. The general synthetic methods of bis-(tetrahydropapaverine) analogues involve tetrahydropapaverine, various piperazines, diisocyanates and diisothiocyanates as starting materials. Pharmacological evaluation involves the in vitro antispasmodic activity on a freshly removed guinea pig ileum using a force displacement transducer amplifier connected to a physiograph. Among the analogues synthesized in the present study, N,N′-bis-[2-carbamoyl-1-(3,4- dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinyl]piperazine (22), was found to be the most potent muscle relaxant (IC50: 0.31 μM).
- Kaur, Jaskiran,Ghosh, Narendra Nath,Chandra, Ramesh
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p. 316 - 321
(2007/10/03)
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- Synthesis of N-substituted piperazinyl carbamoyl and acetyl derivatives of tetrahydropapaverine: potent antispasmodic agents.
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The synthesis and structure-activity-relationship (SAR) for a series of N-substituted piperazinyl carbamoyl 7-15 and piperazinyl acetyl 18-26 derivatives of tetrahydropapaverine have been carried out. The general synthetic methods of carbamoyl tetrahydropapaverine analogues involve N-substituted piperazines and carbamoyl imidazole tetrahydropapaverine as starting materials. Another route for synthesizing these compounds, involving the formation of carbamoyl imidazole piperazine has also been explored. Acylation of tetrahydropapaverine followed by substitution with various piperazinyl moities afforded the acetyl tetrahydropapaverine derivatives. Variously substituted piperazines have been used to monitor the effect of electron releasing and electron withdrawing substituents upon the antispasmodic activity of the molecules. Effect of varying electron densities on the antispasmodic activity, by altering the position of these groups on the benzene ring has also been monitored. Pharmacological methods involve the in vitro antispasmodic activity studies on a freshly removed guinea pig ileum using a force displacement transducer amplifier connected to a physiograph. Among the analogues synthesized in the present study, a promising compound 7, a potent muscle relaxant as compared to papaverine has been obtained.
- Kaur, Jaskiran,Ghosh, Narendra Nath,Talwar, Anita,Chandra, Ramesh
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p. 1223 - 1228
(2007/10/03)
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- Total syntheses of 1-methyl-1,2,3,4-tetrahydronaphtho[2,1-f]isoquinolines involving free radical cyclizations induced by tributyltin(IV) hydride
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We describe two total syntheses of 1-methyl-1,2,3,4-tetrahydronaphtho[1,2-f]isoquinolines based on free radical cyclization. One of them includes the cyclization of N-{2-[2-(2-bromophenyl)-1-methoxyethyl]phenylethyl}acetamides and subsequent transformation of the resulting N-[2-(10-methoxy-9,10-dihydro-1-phenanthryl)ethyl]acetamides. The second is based on the known cyclization of 1-(2-bromobenzyl)isochroman-3-ones to 4,5,6a,7-tetrahydrodibenzo[de,g]chroman-3-ones followed by transformation of the resulting 2-(1-phenanthryl)acetamides.
- Martínez, Elena,Estévez, Juan C,Estévez, Ramón J,Castedo, Luis
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p. 1973 - 1979
(2007/10/03)
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- A rapid and convenient synthesis of amides from aromatic acids and aliphatic amines in dry media under microwave irradiation
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The synthesis of amides 2 from the corresponding aromatic acids and aliphatic amines in the presence of catalytic amount of p-toluenesulfonic acid has been reported. The reactions are accelerated with microwave irradiation under solvent-free conditions to afford a high yielding synthesis of amides.
- Hajipour,Ghasemi
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p. 504 - 507
(2007/10/03)
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- A one-pot bicycloannulation method for the synthesis of tetrahydroisoquinoline systems
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A highly effective method for the synthesis of the core indolo[2,3- α]quinolizidine skeleton found in yohimbine is described. The reaction of N- monosubstituted thioamides with bromoalkenoyl chlorides furnishes thioisomunchnones as transient 1,3-dipoles that undergo ready intramolecular cycloaddition across the tethered π-bond to give thio-bicycloannulated products in a one-pot operation. The stereochemical outcome of the intramolecular reaction is the consequence of an endo cycloaddition of the neighboring π-bond across the transient thioisomunchnone dipole. A major limitation of the method is that when a hydrogen is present in the α- position of the thioamide the initially formed thio-N-acyliminium ion undergoes proton loss to produce a S,N-ketene acetal at a faster rate than dipole formation. Treatment of tetrahydro-β-carboline-1-thione with 2- bromooct-7-enoyl chloride followed by reductive removal of sulfur from the cycloadduct resulted in the formation of (±)-alloyohimbanone. Attempts to cycloadd the thioisomunchnone dipole across several nucleophilic π-bonds failed, and instead, products derived from cyclization of the π-bond onto the initially formed thio-N-acyliminium ion were formed. The resulting N,S- ketals were further converted into several tetrahydroisoquinoline alkaloids in good yield.
- Padwa, Albert,Beall, L. Scott,Heidelbaugh, Todd M.,Liu, Bing,Sheehan, Scott M.
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p. 2684 - 2695
(2007/10/03)
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- Piperazine derivatives
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A compound represented by formula (I): STR1 wherein Q represents an aryl group, a heterocyclic group, a diarylmethyl group, an aralkyl group composed of an aryl group and an alkylene group, an alkyl group or a cycloalkyl group, in which the aryl group, heterocyclic group, and the aryl moiety of the diarylmethyl group and aralkyl group may be substituted with one or more substituents; R represents a bicyclic, substituted, nitrogen-containing heterocyclic group or a substituted phenyl group, in which the nitrogen-containing heterocyclic group is composed of a 5-membered, substituted, aromatic or saturated ring containing one or two nitrogen atoms and a 6-membered ring; and Z represents an alkylene group, an alkenylene group, an alkylene group, a carbonyl group, an alkylene group containing a carbonyl group or an oxalyl group, or a salt thereof. The compound has calmodulin inhibitory activity and is useful as a treating agent for diseases in the circulatory organs or in the cerebral region which are caused by excessive activation of calmodulin.
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- Coralyne and related compounds as mammalian topoisomerase I and topoisomerase II poisons
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DNA topoisomerases are nuclear enzymes responsible for modifying the topological state of DNA. The development of agents capable of poisoning topoisomerases has proved to be an attractive approach in the search for novel cancer chemotherapeutics. Coralyne, an antileukemic alkaloid, has appreciable structural similarity to the potent topoisomerase I and II poison, nitidine. Analogues of coralyne were synthesized and evaluated for their activity as topoisomerase I and topoisomerase II poisons. These analogues were also evaluated for cytotoxicity in the human lymphoblast cell line, RPMI 8402, and its camptothecin-resistant variant, CPT-K5. The pharmacological activity of these analogues exhibited a strong dependence on the substitution pattern and the nature of substituents. Several 1- benzylisoquinolines and 3-phenylisoquinolines were also synthesized. These compounds, which incorporate only a portion of the ring structure of coralyne, were evaluated as topoisomerase poisons and for cytotoxicity. These structure-activity studies indicate that the structural rigidity associated with the coralyne ring system may be critical for pharmacological activity. The presence of a 3,4-methylenedioxy substituent on these coralyne analogues was generally associated with enhanced activity as a topoisomerase poison. 5,6-Dihydro-3,4-methylenedioxy-10,11-dimethoxydibenzo[a,g]quinolizinium chloride was the most potent topoisomerase I poison among the coralyne analogues evaluated, having similar activity to camptothecin. This analogues also possessed exceptional potency as a topoisomerase II poison. Despite the pronounced activity of several of these coralyne derivatives as topoisomerase I poisons, mine of these compounds had cytotoxic activity similar to camptothecin. Possible differences in cellular absorption between these coralyne analogs, which possess a quaternary ammonium group, and camptothecin may be responsible for the differences observed in their relative cytotoxicity.
- Makhey, Darshan,Gatto, Barbara,Yu, Chiang,Liu, Angela,Liu, Leroy F.,LaVoie, Edmond J.
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p. 781 - 791
(2007/10/03)
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- Piperazine derivatives useful as calmodolin inhibitors
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A compound represented by formula (I): wherein Q represents an aryl group, a heterocyclic group, a diarylmethyl group, an aralkyl group composed of an aryl group and an alkylene group, an alkyl group or a cycloalkyl group, in which the aryl group, heterocyclic group, and the aryl moiety of the diarylmethyl group and aralkyl group may be substituted with one or more substituents; R represents a bicyclic, substituted, nitrogen-containing heterocyclic group or a substituted phenyl group, in which the nitrogen-containing heterocyclic group is composed of a 5-membered, substituted, aromatic or saturated ring containing one or two nitrogen atoms and a 6-membered ring; and Z represents an alkylene group, an alkenylene group, an alkylene group, a carbonyl group, an alkylene group containing a carbonyl group or an oxalyl group,or a salt thereof. The compound has calmodulin inhibitory activity and is useful as a treating agent for diseases in the circulatory organs or in the cerebral region which are caused by excessive activation of calmodulin.
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- Synthesis and Photo-oxygenation of Some Substituted 1-Benzyl-3,4-dihydroisoquinolines. Mechanism of Enamine Photo-oxygenation
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The synthesis of a series of substituted 1-benzyl-3,4-dihydroisoquinolines by Bischler-Napieralski cyclization is described.Competitive methylene blue sensitized photo-oxygenation experiments allowed the determination of relative rates of photo-oxygenation of 1-benzyl-3,4-dihydroisoquinolines.Substituents were shown to affect both the equilibrium concentration of the tautomeric enamine and the overall photo-oxygenation rate.After correcting for differences in enamine concentration, the relative rate data provided a diagnostic probe of the reaction mechanism, which involves transfer of charge in the rate-limiting step.
- Martin, Ned H.,Jefford, Charles W.
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p. 762 - 774
(2007/10/02)
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- Hofmann Degradation of β-Hydroxy Ammonium Salts. α- and β-Hydroxylaudanosine, 7-Hydroxyglaucine, and 13-Hydroxyxylopinine
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The four related β-hydroxy ammonium methiodide salts of α-hydroxylaudanosine (2a), β-hydroxylaudanosine (2b), 7-hydroxyglaucine (5a), and 13-hydroxyxylopinine (8a) have been subjected to Hofmann degradation.Although precedent dictates that such materials should form either epoxides or ketones, these are not found.Only products of (a) fragmentation and elimination (from 2a and 2b), (b) dehydration and elimination (from 5a), and (c) elimination and oxidation (from 8a) are obtained.The results are accounted for by consideration of the molecular geometries of theβ-hydroxy ammonium salts as experimentally determined from single-crystal X-ray studies and the geometric requirements for epoxide and ketone formation.
- Wert, Kathleen L.,Chackalamannil, Samuel,Miller, Eric,Dalton, David R.,Zacharias, David E.,Glusker, Jenny P.
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p. 5141 - 5150
(2007/10/02)
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- Oxazoles in Organic Chemistry. 2. Application to the Synthesis of Benzylisoquinoline Alkaloids
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A conceptually new route to the benzylisoquinoline alkaloids has been devised.The reaction of 2-lithiooxazoles with aromatic aldehydes to generate the thermodynamically favored 2-substituted oxazoles constitutes the key step in this process.A single-pot two carbon-carbon bond-joining reaction leading to an oxazoline suitable for further transformation to a phenethylamide is also described.
- Kozikowski, Alan P.,Ames, Anthony
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p. 2548 - 2550
(2007/10/02)
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- Oxidative Coupling of Phenols and Phenolic Ethers. Part 4. Synthesis of Dibenzazonines and a Dibenzazecine, via Direct Coupling
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Two series of amides, N-phenethylphenylacetamides (9) and the bisphenetylamides (11), including diphenolic monophenolic, and non-phenolic types, were treated with a range of one-electron oxidants.With the tetramethoxy-derivative (11e) intramolecular coupling yielded a dibenzazonine (16) in 36percent yield.Similar oxidation of the homologue (18) gave a dibenzazecine (19) in 60percent yield.
- McDonald, Edward,Wylie, Robert D.
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p. 1104 - 1108
(2007/10/02)
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