- 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; 00246
(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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- Copper(ii)-catalyzed and acid-promoted highly regioselective oxidation of tautomerizable C(sp3)-H bonds adjacent to 3,4-dihydroisoquinolines using air (O2) as a clean oxidant
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A mild, efficient and eco-friendly method for the oxidation of 1-Bn-DHIQs to 1-Bz-DHIQs without concomitant excessive oxidation of 1-Bz-DHIQs to 1-Bz-IQs is very important for the syntheses of 1-Bz-DHIQ alkaloids and analogues. In this article, we developed a novel Cu(ii)-catalyzed and acid-promoted highly regioselective oxidation of tautomerizable C(sp3)-H bonds adjacent to the C-1 positions of various 1-Bn-DHIQs. It was observed that when 0.2 equiv. of Cu(OAc)2·2H2O was used as the catalyst, 3.0 equiv. of AcOH was used as the additive and air (O2) was used as a clean oxidant, various 1-Bn-DHIQs could be efficiently oxidized to corresponding 1-Bz-DHIQs at 25 °C in DMSO. Especially, almost no concomitant excessive oxidation of 1-Bz-DHIQs to 1-Bz-IQs was observed during the above reaction. In addition, this method was successfully applied in the first total synthesis of the alkaloid canelillinoxine.
- Fan, Qi-Qi,He, Yun-Gang,Huang, Yong-Kang,Luo, Yong-Qiang,Shi, Xiao-Xin,Zheng, Bo,Zhu, Xing-Liang
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p. 29702 - 29710
(2021/10/08)
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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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- Development of Pd(OAc)2-catalyzed tandem oxidation of C[sbnd]N, C[sbnd]C, and C(sp3)–H bonds: Concise synthesis of 1-aroylisoquinoline, oxoaporphine, and 8-oxyprotoberberine alkaloids
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A catalytic tandem oxidation of C[sbnd]N, C[sbnd]C, and C(sp3)–H bonds is developed. This tandem oxidation is applied to two-step total syntheses of papaveraldine and pulcheotine A. Additionally, the total synthesis of liriodenine is achieved in six steps from homopiperonyl alcohol and 2-bromophenylacetonitrile by applying this catalytic tandem oxidation. Moreover, the direct conversion of xylopinine to 8-oxypseudopalmatine in a 76% yield demonstrates the versatility of this catalytic reaction.
- Nishimoto, Saeko,Nakahashi, Hiromichi,Toyota, Masahiro
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supporting information
(2020/11/13)
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- Driving Recursive Dehydration by PIII/PV Catalysis: Annulation of Amines and Carboxylic Acids by Sequential C-N and C-C Bond Formation
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A method for the annulation of amines and carboxylic acids to form pharmaceutically relevant azaheterocycles via organophosphorus PIII/PV redox catalysis is reported. The method employs a phosphetane catalyst together with a mild bromenium oxidant and terminal hydrosilane reductant to drive successive C-N and C-C bond-forming dehydration events via the serial action of a catalytic bromophosphonium intermediate. These results demonstrate the capacity of PIII/PV redox catalysis to enable iterative redox-neutral transformations in complement to the common reductive driving force of the PIII/PV couple.
- Lecomte, Morgan,Lipshultz, Jeffrey M.,Kim-Lee, Shin-Ho,Li, Gen,Radosevich, Alexander T.
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supporting information
p. 12507 - 12512
(2019/09/04)
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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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- 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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- Preparation methods of papaverine and papaverine hydrochloride
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The invention discloses a preparation method of papaverine. The preparation method comprises 1, dissolving 3, 4-dihydropapaverine hydrochloride in water and adjusting pH of the solution to greater than 7, 2, through trimethylbenzene, carrying out extraction on the aqueous solution obtained through the step 1, and 3, adding a dehydrogenation reaction catalyst into the obtained organic phase, carrying out a dehydrogenation reaction process at a temperature of 50-180 DEG C and then treating the product to obtain papaverine. The invention also discloses a method for preparing papaverine hydrochloride from the papaverine. Through use of trimethylbenzene as a dehydrogenation reaction solvent, a dehydrogenation reaction temperature is reduced, peroxide production is avoided and production safety is greatly improved. The preparation method realizes recycle of trimethylbenzene and reduces a production cost of papaverine or papaverine hydrochloride.
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Paragraph 0036; 0037
(2016/11/28)
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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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- 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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- 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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- 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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- Synthesis of 8-oxoberbines and related benzolactams by Pd(OAc) 2-catalyzed direct aromatic carbonylation
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A variety of alkoxy-substituted benzolactams with a berbine or yohimbane skeleton were prepared from 1-benzyl-1,2,3,4-tetrahydroisoquinolines or 1-benzyl-1,2,3,4-tetrahydro-β-carbolines by a phosphine-free Pd(II)-catalyzed direct aromatic carbonylation in a Pd(OAc)2-Cu(OAc) 2 catalytic system. The site selectivity was compared with that of the carbonylation with Pd(OAc)2 or Pd(OAc)2·2 PPh3, respectively.
- Miyazawa, Mamoru,Tokuhashi, Takashi,Horibata, Akiyoshi,Nakamura, Takatoshi,Onozaki, Yu,Kurono, Nobuhito,Senboku, Hisanori,Tokuda, Masao,Ohkuma, Takeshi,Orito, Kazuhiko
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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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experimental part
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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- Enantioselective synthesis of tetrahydroprotoberberines and bisbenzylisoquinoline alkaloids from a deprotonated α-aminonitrile
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Under controlled conditions, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline- 1-carbonitrile can be quantitatively deprotonated in the α-position. Its alkylation directly furnishes 3,4-dihydroisoquinolines which can serve as starting materials for the preparation of various alkaloids. Here, the preparation of the benzylisoquinolines (+)-laudanidine, (+)-armepavine, and (+)-laudanosine as well as the tetrahydroprotoberberines ( - )-corytenchine and ( - )-tetrahydropseudoepiberberine using Noyori's asymmetric transfer hydrogenation are described. The dimeric alkaloids (+)-O-methylthalibrine and (+)-tetramethylmagnolamine were obtained from nonracemic precursors in Ullmann diaryl ether syntheses.
- Blank, Nancy,Opatz, Till
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experimental part
p. 9777 - 9784
(2012/01/30)
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- Oxidation of 1-benzyldihydroisoquinolines or 1- benzyltetrahydroisoquinolines with dioxygen to 1-benzoylisoquinolines
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An environmental-benign methodology to synthesize 1-benzoylisoquinolines from 1-benzyl-3, 4-dihydroisoquinolines or 1-benzyl-1,2,3,4- tetrahydroisoquinolines using dioxygen as an oxidant was developed. This methodology in combination with Bischler-Napieralski reaction leads to a facile synthesis of 1-benzoylisoquinolines from phenylacetic acids and phenylethanamines.
- Gan, Haifeng,Lu, Yunyu,Huang, Yue,Ni, Lijun,Xu, Jinyi,Yao, Hequan,Wu, Xiaoming
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scheme or table
p. 1320 - 1324
(2011/04/15)
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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 89
(2010/07/09)
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- New synthesis of 1-[(3,4-dimethoxyphenyl)methoxymethyl]-6,7-dimethoxyisoquinoline (setigerine), a naturally occurring alkaloid, and some derivatives of papaverine
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A novel and improved synthetic route for the preparation of the new alkaloid setigerine, isolated from Papaver setigerum DC, and some new 3,4-dihydropapaverine and papaverine derivatives is reported. This method is based on the side chain chlorination of 1-benzyl-3,4-dihydroisoquinolines using N-chlorosuccinimide (NCS) and subsequent reaction with sodium methoxide in methanol to give the corresponding isoquinolines.
- Jacobs, Jan,van Tuyen, Nguyen,Markusse, Peter,Stevens, Christian V.,Maat, Leendert,De Kimpe, Norbert
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experimental part
p. 1188 - 1192
(2009/04/10)
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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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- Synthesis of lamellarin U and lamellarin G trimethyl ether by alkylation of a deprotonated α-aminonitrile
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(Chemical Equation Presented) 1,2,3,4-Tetrahydroisoquinoline-1- carbonitriles can serve as starting materials for the one-pot synthesis of 5,6-dihydropyrrolo[2,1a]isoquinolines and 1-benzyl-3,4-dihydroisoquinolines. The latter compounds were transformed to lamellarin G trimethyl ether and lamellarin U in short reaction sequences. This method allows the introduction of acid-sensitive protecting groups for the phenolic hydroxy functions which would be cleaved under the harsh conditions of the classical Bischler-Napieralski reaction.
- Liermann, Johannes C.,Opatz, Till
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p. 4526 - 4531
(2008/09/21)
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- Synthesis of (-)-(S)-norlaudanosine, (+)-(R)-O,O-dimethylcoclaurine, and (+)-(R)-salsolidine by alkylation of an α-aminonitrile
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A short asymmetric synthesis of 1-substituted 1,2,3,4- tetrahydroisoquinoline alkaloids by deprotonation of an unprotected α-aminonitrile and alkylation of the resulting carbanion followed by spontaneous elimination of HCN and asymmetric reduction is described. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Werner, Frank,Blank, Nancy,Opatz, Till
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p. 3911 - 3915
(2008/02/13)
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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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- Enantioselective synthesis of (+)-(S)-laudanosine and (-)-(S)-xylopinine
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The study presents a new pathway for the enantioselective synthesis of benzylisoquinoline alkaloids. The key steps of the synthesis of (+)-(S)-laudanosine (1) and (-)-(S)-xylopinine (2) are a Sonogashira coupling that builds up the C1-C8a bond of the benzylisoquinoline skeleton, an intramolecular Ti-catalyzed hydroamination of an alkyne, and a subsequent enantioselective imine reduction according to Noyori's protocol.
- Mujahidin, Didin,Doye, Sven
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p. 2689 - 2693
(2007/10/03)
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- Synthesis of (±)-Glaucine and (±)-Neospirodienone via an One-Pot Bischler-Napieralski Reaction and Oxidative Coupling by a Hypervalent Iodine Reagent
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Condensation of 3,4-dimethoxybenzeneethanamine (3d) and various benzeneacetic acids, i.e., 4a-e, via a practical and efficient one-pot Bischler-Napieralski reaction, followed by NaBH4 reduction, produced a series of 1-benzyl-1,2,3,4-tetrahydroisoquinolines, i.e., 5a-e, in satisfactory yields (Scheme 3). Oxidative coupling of the N-acyl and N-methyl derivatives 6a-e of the latter with hypervalent iodine ([IPh(CF 3COO)2]) yielded products with two different skeletons (Scheme 4). The major products from N-acyl derivatives 6a-c were (±)-N-acylneospirodienones 2a-c, while the minor was the 3,4-dihydroisoquinoline 7. (±)-Glaucine (1), however, was the major product starting from N-methyl derivative 6e. Possible reaction mechanisms for the formation of these two types of skeleton are proposed (Scheme 5).
- Huang, Wei-Jan,Singh, Om V.,Chen, Chung-Hsiung,Lee, Shoei-Sheng
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p. 167 - 174
(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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- Synthesis of isoquinolines from 2-phenylethylamines, amides, nitriles and carboxylic acids in polyphosphoric acid
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A convenient one pot synthesis of 1-, 1.3-substituted 3,4-dihydroisoquinolines 5 enamines 10 and 3-oxo-2,3-dihydroisoquinolines 18 as well as of enamides 22 of isoquinoline from 2-phenyl-, 1,2-diphenylethylamines, phenylacetamides, phenylacetonitriles, N-acylphenylethylamines and carboxylic acids in nonaqueous media has been accomplished.
- Venkov, Atanas P.,Ivanov, Ilian I.
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p. 12299 - 12308
(2007/10/03)
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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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- Pharmaceutical compositions containing isoquinoline derivatives
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Pharmaceutical compositions containing an isoquinoline derivative exhibit an excellent inhibitory action to an isozyme of phosphodiesterase of the type IV (PDEIV). The active component of the pharmaceutical composition is an isoquinoline derivative which is represented by the general formula: STR1 wherein R is an ethoxy group, or which is a pharmaceutically-acceptable salt of a compound represented by said formula. The isoquinoline derivatives have an excellent inhibitory action which is highly specific to PDEIV. They are highly useful as pharmaceuticals such as antidepressive agents, tranquilizers, antidemential agents, antiinflammatory agents, antiallergic agents, antiasthmatic agents, liver-protecting agents, and diuretic agents.
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- Selective inhibition of calcium entry induced by benzylisoquinolines in rat smooth muscle
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The mechanism of relaxant activity of six benzylisoquinolines was examined in order to determine the minimal structural requirements that enable these compounds to have either a non-specific action like papaverine or an inhibitory activity on calcium entry via potential-operated channels. All the alkaloids tested totally or partially relaxed KCl-depolarized rat uterus and inhibited oxytocin-induced rhythmic contractions. Only glaucine and laudanosine inhibited K+-induced uterine contractions more than oxytocin-induced uterine contractions. In Ca+-free medium, sustained contractions induced by oxytocin or vanadate were relaxed by the alkaloids tested except for glaucine and laudanosine indicating no inhibitory effect on intracellular calcium release. Those alkaloids containing an unsaturated heterocyclic ring (papaverine, papaverinol, papaveraldine, N-methylpapaverine and dehydropapaverine) exhibited a more specific activity than those with a tetrahydroisoquinoline ring.
- Anselmi,Fayos,Blasco,Candenas,Cortes,D'Ocon
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p. 337 - 343
(2007/10/02)
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- Reactions of 1,2,3,4-Tetrahydroisoquinoline Derivatives with Sulfur
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1,2,3,4-Tetrahydroisoquinolines react with sulfur in pyridine to give two different types of products, depending on the structure of the starting compounds. 1-Substituted derivatives 1 undergo partial dehydrogenation with formation of the corresponding 3,4-dihydroisoquinolines 3. 1,2,3,4-Tetrahydroisoquinolines 5 bearing no substituent in 1-position yield the 3,4-dihydro-1(2H)isoquinolinethiones 6, comprising a new and simple synthesis of compounds 6.
- Ajzert, Ilona K.,Takacs, Kalman
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p. 1061 - 1064
(2007/10/02)
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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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- SYTHESIS OF N-(ARYLETHYL)ARYLTHIOACETAMIDES BY THE WILLGERODT-KINDLER REACTION AND THEIR CONVERSION TO SUBSTITUTED 1-BENZYL-1,2,3,4-TETRAHYDROISOQUINOLINES
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N-(Arylethyl)arylthioacetamides were synthesized by the reaction of substituted acetophenones with 2-arylethylamines.The reaction gives good yields when compounds with substituted hydroxyl groups are used. 2,4-Diarylthiazoles were isolated as side products from the Wilgerodt-Kindler reaction.The thioamides were converted into substituted 1-benzyl-1,2,3,4-tetrahydroisoquinolines by the Bischler-Napieralski cyclization, N-methylation, and reduction of the corresponding 3,4-dihydroisoquinoline methiodide derivatives.
- Nakova, E.P.,Tolkachev, O.N.,Evstigneeva, R.P.
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p. 550 - 555
(2007/10/02)
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