- Discovery of 4-((2 S,4 S)-4-Ethoxy-1-((5-methoxy-7-methyl-1 H-indol-4-yl)methyl)piperidin-2-yl)benzoic Acid (LNP023), a Factor B Inhibitor Specifically Designed to Be Applicable to Treating a Diverse Array of Complement Mediated Diseases
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The alternative pathway (AP) of the complement system is a key contributor to the pathogenesis of several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. The serine protease factor B (FB) is a key node in the AP and is integral to the formation of C3 and C5 convertase. Despite the prominent role of FB in the AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we describe in more detail our efforts to identify FB inhibitors by high-throughput screening (HTS) and leveraging insights from several X-ray cocrystal structures during optimization efforts. This work culminated in the discovery of LNP023 (41), which is currently being evaluated clinically in several diverse AP mediated indications.
- Mainolfi, Nello,Ehara, Takeru,Karki, Rajeshri G.,Anderson, Karen,Mac Sweeney, Aengus,Liao, Sha-Mei,Argikar, Upendra A.,Jendza, Keith,Zhang, Chun,Powers, James,Klosowski, Daniel W.,Crowley, Maura,Kawanami, Toshio,Ding, Jian,April, Myriam,Forster, Cornelia,Serrano-Wu, Michael,Capparelli, Michael,Ramqaj, Rrezarta,Solovay, Catherine,Cumin, Frederic,Smith, Thomas M.,Ferrara, Luciana,Lee, Wendy,Long, Debby,Prentiss, Melissa,De Erkenez, Andrea,Yang, Louis,Liu, Fang,Sellner, Holger,Sirockin, Finton,Valeur, Eric,Erbel, Paulus,Ostermeier, Daniela,Ramage, Paul,Gerhartz, Bernd,Schubart, Anna,Flohr, Stefanie,Gradoux, Nathalie,Feifel, Roland,Vogg, Barbara,Wiesmann, Christian,Maibaum, Jürgen,Eder, J?rg,Sedrani, Richard,Harrison, Richard A.,Mogi, Muneto,Jaffee, Bruce D.,Adams, Christopher M.
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Read Online
- Preparation method of dimethyl carbamoyl chloride
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The invention relates to a preparation method of dimethyl carbamoyl chloride, which is characterized in that dimethyl carbamoyl chloride is directly synthesized by dimethylamine chloride and carbon monoxide under the action of a catalyst, the catalyst is optimized, and a special reactor is designed, so that efficient and green production of the dimethyl carbamoyl chloride is realized. The invention provides an efficient and green intermediate synthesis method for synthesis of pesticides pirimicarb and triazamate and a large number of pesticides.
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Paragraph 0036-0044
(2021/05/12)
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- Dual inhibitors of Interleukin-6 and acetylcholinesterase for treatment of Alzheimer's disease: Design, docking, synthesis and biological evaluation
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Multitarget compounds intercept two or more functionally complementary pathways simultaneously, and are therefore considered to have potential in effectively treating complex multifactorial diseases like Alzheimer's disease (AD). In the present study, novel molecules are designed by coupling a chromone and a N,N-disubstituted carbamoyl amine as pharmacophore for interleukin-6 (IL-6) and acetylcholinesterase (AChE) inhibition, respectively. Four series (Y1–Y4) of 40 compounds are designed by using alkyl linkers of different lengths (1–4 carbon atoms) for the coupling of the two selected pharmacophore. Docking of all designed compounds in AChE leads to the identification of twelve best fit compounds (Docking score >8.3). The data suggests that a 1- or 2-carbon atom linker is the most conducive to orient the pharmacophore for optimum binding with AChE active site. The predicted ADME properties of the 12 selected compounds suggest that these can cross the blood brain barrier (BBB) with good oral bioavailability. These compounds are synthesised and evaluated for anti-AChE activity. Five compounds, showing >45% inhibition of AChE, are further evaluated for IL-6 inhibitory activity. Compound Y1f is found to be the most potent inhibitor of both AChE and IL-6 (IC50 0.7 and 0.8 ?μM, respectively). It suggests that a chromone moiety connected to a piperidine ring through a 1-carbon atom linker may provide a useful template to medical chemists for the development of new chemical entities effective against AD.
- Bansal, Yogita,Kaur, Sukhvir
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- Cannabidiol carbamate compound, pharmaceutical preparation, preparation method and application
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The invention relates to a cannabidiol carbamate compound, a medicinal preparation, a preparation method and application, and belongs to the field of compounds for treating and preventing diseases related to aging, Alzheimer's disease and Parkinson's disease. The compound has a structure shown as a formula I or a pharmaceutically acceptable salt of the structure shown as the formula I. The compound has good butyrylcholine esterase resisting activity, shows good application prospect in treatment of Alzheimer's disease, and shows good application potential.
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Paragraph 0087-0091
(2021/01/30)
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- Synthesis and Biological Evaluation of Celastrol Derivatives with Improved Cytotoxic Selectivity and Antitumor Activities
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Cdc37 associates kinase clients to Hsp90 and promotes the development of cancers. Celastrol, a natural friedelane triterpenoid, can disrupt the Hsp90-Cdc37 interaction to provide antitumor effects. In this study, 31 new celastrol derivatives, 2a - 2d , 3a - 3g , and 4a - 4t , were designed and synthesized, and their Hsp90-Cdc37 disruption activities and antiproliferative activities against cancer cells were evaluated. Among these compounds, 4f , with the highest tumor cell selectivity (15.4-fold), potent Hsp90-Cdc37 disruption activity (IC50= 1.9 μM), and antiproliferative activity against MDA-MB-231 cells (IC50= 0.2 μM), was selected as the lead compound. Further studies demonstrated 4f has strong antitumor activities both in vitro and in vivo through disrupting the Hsp90-Cdc37 interaction and inhibiting angiogenesis. In addition, 4f exhibited less toxicity than celastrol and showed a good pharmacokinetics profile in vivo. These findings suggest that 4f may be a promising candidate for development of new cancer therapies.
- Feng, Jia-Hao,He, Qi-Wei,Hou, Ji-Qin,Hu, Xiao-Long,Long, Huan,Wang, Bao-Lin,Wang, Hao,Wang, Quan,Wang, Rong,Ye, Wen-Cai,Zhang, Li-Xin,Zhang, Xiao-Qi
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p. 1954 - 1966
(2021/07/20)
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- Novel cannabidiol?carbamate hybrids as selective BuChE inhibitors: Docking-based fragment reassembly for the development of potential therapeutic agents against Alzheimer's disease
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Cannabidiol (CBD) and rivastigmine have been launched as drugs for treating dementia and cholinesterases (ChEs) are ideal drug targets. This study focused on developing novel ChE inhibitors as drug leads against dementia through molecular modeling and fragment reassembly approaches. A potent carbamate fragment binding to active site gorge of BuChE was found via a docking-based structural splicing approach, thus, 17 novel compounds were designed by structural reassembly. Compound C16 was identified as a highly selective potent BuChE inhibitor (IC50 = 5.3 nM, SI > 4000), superior to CBD (IC50 = 0.67 μM). C16 possessed BBB penetrating ability, benign safety, neuroprotection, antioxidant and pseudo-irreversible BuChE inhibition (Kd = 13 nM, k2 = 0.26 min?1), showing good drug-like properties. In vivo studies confirmed that C16 significantly ameliorated the scopolamine-induced cognition impairment, almost entirely recovered the Aβ1?42 (icv)-impaired cognitive function to the normal level, showed better behavioral performance than donepezil and good anti-amyloidogenic effect. Hence, the potential BuChE inhibitor C16 can be developed as a promising disease-modifying treatment of AD.
- Jiang, Xia,Liu, Xin-Hua,Shi, Jingbo,Tang, Wenjian,Wang, Sheng,Wu, Chengyao,Xu, Yingying,Zha, Liang,Zhang, Jing,Zhang, Ziwen,Zuo, Jiawei
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- Preparation method of dimethylcarbamoyl chloride
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The invention discloses a preparation method of dimethylcarbamoyl chloride. The preparation method comprises the following steps: simultaneously introducing dimethylamine and phosgene into a micro-reactor to perform the reaction to obtain the dimethylcarbamoyl chloride. The dimethylcarbamoyl chloride prepared in the preparation method disclosed by the invention is high in content, the content reaches 98.5 to 99 percent, and the yield is greatly increased and can reach 95.0 to 96.2 percent (referring to dimethylamine). The preparation method disclosed by the invention has the advantages of simple operation, high yield, less waste, safety, environmental protection and the like, is suitable for industrialized production and good in application value and application prospect.
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Paragraph 0023-0034
(2019/03/08)
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- Design, synthesis and biological evaluation of dual acetylcholinesterase and phosphodiesterase 5A inhibitors in treatment for Alzheimer's disease
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With the recent research advances in molecular biology and technology, multiple credible hypotheses about the progress of Alzheimer's disease (AD) have been proposed; multi-target drugs have emerged as an innovative therapeutic approach for AD. Current clinical therapy for AD patients is mainly palliative treatment targeting acetylcholinesterase (AChE). Inhibition of phosphodiesterase 5A (PDE5A) has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). In this work, series of new compounds were designed, synthesized and evaluated as dual cholinesterase and PDE5A inhibitor. Biological results revealed that some of these compounds display good biological activities against AChE with IC50 values about 44.67–169.80 nM (donepezil IC50 50.12 nM). Notably, compound 12 presented potent activities against PDE5A with IC50 values about 50 μM (sildenafil IC50 12.59 μM), and some of these compounds showed low cell toxicity to A549 cells in vitro.
- Zhou, Li-yun,Zhu, Yao,Jiang, Yu-ren,Zhao, Xiong-jie,Guo, Dong
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supporting information
p. 4180 - 4184
(2017/08/23)
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- Design, synthesis and biological evaluation of 4'-aminochalcone-rivastigmine hybrids as multifunctional agents for the treatment of Alzheimer's disease
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A series of 4'-aminochalcone-revastigmine hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. The results showed that most of these compounds exhibited good multifunctional activities. In particular, compound 6c displayed the best inhibitory potency on acetylcholinesterase (IC50= 4.91 μM), and significant antioxidative activity with a value 2.83-fold of Trolox. The kinetic analysis of AChE inhibition revealed that 6c showed mixed-type inhibition, binding simultaneously to the catalytic active site and peripheral anionic site of AChE. In addition, 6c inhibited self-induced Aβ1-42aggregation and Cu2+-induced Aβ1-42aggregation by 89.5% and 79.7% at 25 μM respectively, as well as acted as a selective monoamine oxidase B inhibitor (IC50= 0.29 μM) and a selective biometal chelator. Furthermore, 6c could cross the blood-brain barrier in vitro. Based on these results, Compound 6c could be considered as a very promising lead compound for Alzheimer's disease.
- Xiao, Ganyuan,Li, Yan,Qiang, Xiaoming,Xu, Rui,Zheng, Yunxiaozhu,Cao, Zhongcheng,Luo, Li,Yang, Xia,Sang, Zhipei,Su, Fu,Deng, Yong
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p. 1030 - 1041
(2017/02/05)
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- One-Pot Synthesis of O -Aryl Carbamates
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A simple, versatile, one-pot procedure for the synthesis of substituted O-aryl carbamates has been developed, and a protocol is henceforth described. N-Substituted carbamoyl chloride is formed in situ and subsequently reacted with a substituted phenol, avoiding the direct manipulation of sensitive reactants. This procedure offers an economical and efficient route to many compounds of interest.
- Varjosaari, Sami E.,Suating, Paolo,Adler, Marc J.
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- Design, Synthesis, and Biological Evaluation of Scutellarein Derivatives Based on Scutellarin Metabolic Mechanism in Vivo
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Three series of scutellarein derivatives have been designed and synthesized based on metabolic mechanism of scutellarin (1) in vivo. Their thrombin inhibition activities were tested through the analyzation of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen (FIB). The antioxidant activities of these target products were assessed by 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) assay and the ability to protect PC12 cells against H2O2-induced cytotoxicity, and their solubilities were evaluated by ultraviolet (UV) spectrophotometer. The results showed that the two isopropyl groups substituted derivative (18c) demonstrated stronger anticoagulant activity, better water solubility, and good antioxidant activity compared with scutellarein (2), which warrants further development of 18c as a promising agent for ischemic cerebrovascular disease treatment. Three series of scutellarein derivatives have been designed and synthesized based on metabolic mechanism of scutellarin (1) in vivo. The results of the biological evaluation showed that the two isopropyl groups substituted derivative (18c) demonstrated stronger anticoagulant activity, better water solubility, and good antioxidant activity compared with scutellarein (2), which warrants further development of 18c as a promising agent for ischemic cerebrovascular disease treatment.
- Dong, Ze-Xi,Shi, Zhi-Hao,Li, Nian-Guang,Zhang, Wei,Gu, Ting,Zhang, Peng-Xuan,Wu, Wen-Yu,Tang, Yu-Ping,Fang, Fang,Xue, Xin,Li, He-Min,Cheng, Hai-Bo,Yang, Jian-Ping,Duan, Jin-Ao
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p. 946 - 957
(2016/05/24)
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- Optimization of 1,2,5-thiadiazole carbamates as potent and selective ABHD6 inhibitors
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At present, inhibitors of α/β-hydrolase domain 6 (ABHD6) are viewed as a promising approach to treat inflammation and metabolic disorders. This article describes the development of 1,2,5-thiadiazole carbamates as ABHD6 inhibitors. Altogether, 34 compounds were synthesized, and their inhibitory activity was tested using lysates of HEK293 cells transiently expressing human ABHD6 (hABHD6). Among the compound series, 4-morpholino-1,2,5-thiadiazol-3-yl cyclooctyl(methyl)carbamate (JZP-430) potently and irreversibly inhibited hABHD6 (IC50 = 44 nM) and showed ～ 230-fold selectivity over fatty acid amide hydrolase (FAAH) and lysosomal acid lipase (LAL), the main off-targets of related compounds. Additionally, activity-based protein profiling indicated that JZP-430 displays good selectivity among the serine hydrolases of the mouse brain membrane proteome. JZP-430 has been identified as a highly selective, irreversible inhibitor of hABHD6, which may provide a novel approach in the treatment of obesity and type II diabetes.
- Patel, Jayendra Z.,Nevalainen, Tapio J.,Savinainen, Juha R.,Adams, Yahaya,Laitinen, Tuomo,Runyon, Robert S.,Vaara, Miia,Ahenkorah, Stephen,Kaczor, Agnieszka A.,Navia-Paldanius, Dina,Gynther, Mikko,Aaltonen, Niina,Joharapurkar, Amit A.,Jain, Mukul R.,Haka, Abigail S.,Maxfield, Frederick R.,Laitinen, Jarmo T.,Parkkari, Teija
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p. 253 - 265
(2015/02/05)
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- Synthesis of scutellarein derivatives to increase biological activity and water solubility
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In order to improve the biological activity and water solubility of scutellarin (1), some derivatives of its main metabolite (scutellarein) were designed and synthesized. All the compounds were tested for their thrombin inhibition activity through the analyzation of thrombin time (TT), activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrinogen (FIB). Their antioxidant activities were assessed by measuring their scavenging capacities toward 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and the ability to protect PC12 cells against H2O2-induced cytotoxicity, their water solubility were also assessed by ultraviolet (UV) spectrophotometer. The results showed that compound 8b demonstrated stronger anticoagulant and antioxidant activity, better water solubility compared with scutellarein (2), which warrants it as a promising agent for the treatment of ischemic cerebrovascular disease.
- Shi, Zhi-Hao,Li, Nian-Guang,Shi, Qian-Ping,Zhang, Wei,Dong, Ze-Xi,Tang, Yu-Ping,Zhang, Peng-Xuan,Gu, Ting,Wu, Wen-Yu,Fang, Fang,Xin-Xue,Li, He-Min,Yang, Jian-Ping,Duan, Jin-Ao
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p. 6875 - 6884
(2015/11/11)
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- Synthesis of pterostilbene and resveratrol carbamate derivatives as potential dual cholinesterase inhibitors and neuroprotective agents
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Pterostilbene and resveratrol carbamate derivatives were designed and synthesized by use of a multi-target directed drug-design strategy. Their acetylcholinesterase and butylcholinesterase inhibitory activity and neuroprotective effects against hydrogen peroxide-induced PC12 cell injury were evaluated in vitro. The results indicated that some of the compounds had dual inhibitory potency against acetylcholinesterase and butylcholinesterase, and potential neuroprotective effects, and could be considered as potential multi-target-directed agents.
- Yuan, Wen,Shang, Zhipei,Qiang, Xiaoming,Tan, Zhenghuai,Deng, Yong
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p. 787 - 800
(2014/02/14)
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- Selective and reusable iron(II)-based molecular sensor for the vapor-phase detection of alcohols
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A mononuclear iron(II) neutral complex (1) is screened for sensing abilities for a wide spectrum of chemicals and to evaluate the response function toward physical perturbation like temperature and mechanical stress. Interestingly, 1 precisely detects methanol among an alcohol series. The sensing process is visually detectable, fatigue-resistant, highly selective, and reusable. The sensing ability is attributed to molecular sieving and subsequent spin-state change of iron centers, after a crystal-to-crystal transformation.
- Naik, Anil D.,Robeyns, Koen,Meunier, Christophe F.,Leonard, Alexandre F.,Rotaru, Aurelian,Tinant, Bernard,Filinchuk, Yaroslav,Su, Bao Lian,Garcia, Yann
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supporting information
p. 1263 - 1265
(2014/03/21)
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- A novel and efficient strategy for the synthesis of various carbamates using carbamoyl chlorides under solvent-free and grinding conditions using microwave irradiation
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We present an efficient, fast and simple strategy of generating the intermediate carbamoyl chlorides from secondary amines using stoichiometric amounts of bis(trichloromethyl)carbonate (BTC) in solution and solvent-free conditions with excellent yields. The results obtained showed the yield increasing on whether a base was used. Finally, an efficient and rapid synthesis of variety carbamate derivatives was developed by the reaction with a high variety of different alcohols, phenols, diols and this intermediate at room temperature with grinding and in solvent-free conditions under microwave irradiation. The presence of various safe bases is shown to be effective in reducing the reaction times, increasing the yields and easing purification. The present method does not involve any hazardous phosgene.
- Zare, Hassan,Ghanbari, Mohammad Mehdi,Jamali, Marzieh,Aboodi, Abdollah
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scheme or table
p. 883 - 886
(2012/08/28)
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- Development of an improved method for conversion of thiuram disulfides into N,N-dialkylcarbamoyl halides and derivatives
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A convenient procedure for preparing N,N-disubstituted carbamoyl halides is reported. It consists of two steps: (1) reaction of carbon disulfide and a secondary amine in the presence of a polar organic solvent and oxygen to produce the corresponding tetraalkyl thiuram disulfides and (2) reaction of tetraalkyl thiuram disulfide with a halide in the presence of an aprotic organic solvent to produce the corresponding N,N-disubstituted carbamoyl halide. Copyright Taylor & Francis Group, LLC.
- Adeppa,Rupainwar,Misra, Krishna
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experimental part
p. 285 - 290
(2011/03/20)
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- An improved one-pot cost-effective synthesis of N,N-disubstituted carbamoyl halides and derivatives
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A convenient one-pot procedure is reported for preparing N,N-disubstituted carbamoyl chlorides by using chlorocarbonylsulfenyl chloride as a carbonylating agent. It comprises the reaction of secondary amines with chlorocarbonylsulfenyl chloride in the presence of an aprotic organic solvent to produce the corresponding N,N-disubstituted carbamoyl halides. Insertion of the carbonyl group without using phosgene is the novelty of this method.
- Adeppa,Rupainwar,Misra, Krishna
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experimental part
p. 1277 - 1280
(2011/02/23)
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- Preparation of N,N-Dimethyl-N′-arylureas using S,S-dimethyl dithio-carbonate as a carbonylating reagent
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A new, general method for the preparation of N,N-di-methyl-N′- arylureas using S,S-dimethyl dithiocarbonate as a phosgene substitute is reported. The method has been set up according to four procedures, all including three steps: (1) reaction of S,S-di- methyl dithiocarbonate with dimethylamine to give S-methyl N,N-dimethylthiocarbamate; (2) halogenation with various halogenating reagents (chlorine, methanesulfenyl chloride, bromine, and meth-anesulfenyl bromide) to give N,N-dimethylcarbamoyl chloride or bromide; (3) in situ reaction with primary arylamines. All the target products were obtained in high yields (85-98%; 16 reactions, average yield 93%) and with high purity. Also noteworthy is the recovery of byproducts of industrial interest, namely methanethiol and dimethyl disulfide, with complete exploitation of the reagent S,S- dimethyl dithiocarbonate. Georg Thieme Verlag Stuttgart.
- Degani, Iacopo,Fochi, Rita,Magistris, Claudio,Migliaccio, Mara
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experimental part
p. 801 - 808
(2009/08/07)
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- Semicarbazone-based inhibitors of cathepsin K, are they prodrugs for aldehyde inhibitors?
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Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and 13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.
- Adkison, Kim K.,Barrett, David G.,Deaton, David N.,Gampe, Robert T.,Hassell, Anne M.,Long, Stacey T.,McFadyen, Robert B.,Miller, Aaron B.,Miller, Larry R.,Payne, J. Alan,Shewchuk, Lisa M.,Wells-Knecht, Kevin J.,Willard Jr., Derril H.,Wright, Lois L.
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p. 978 - 983
(2007/10/03)
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- Azepinoindole derivatives as pharmaceutical agents
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Compounds, compositions and methods for modulating the activity of receptors are provided. In particular, compounds and compositions are provided for modulating the activity of receptors and for the treatment, prevention, or amelioration of one or more symptoms of disease or disorder directly or indirectly related to the activity of the receptors.
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- Lactam metalloprotease inhibitors
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The present application describes novel lactams and derivatives thereof of formula I: or pharmaceutically acceptable salt forms thereof, wherein rings ring B is a 4-8 membered cyclic amide containing from 0-3 additional heteroatoms selected from N, O, and S, which are useful as metalloprotease inhibitors.
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- Azulene derivatives
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The invention provides novel azulene derivatives of general formula I wherein R1 to R6 have the significance given in the description, as well as their tautomers, enantiomers, diastereomers, racemates and physiologically compatible salts or esters and substances which are hydrolyzed or metabolized in vivo to compounds of formula I. The invention is also concerned with a process and intermediates for the manufacture of the above compounds, pharmaceutical compositions which contain such compounds as well as the use of these compounds in the treatment of inflammatory conditions.
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- Process for the preparation of 1-4-disubstituted-5 (4H)-tetrazolinones
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1,4-Disubstituted-5(4H)-tetrazolinones of the formula (I) STR1 wherein R1, R2 and R3 have the meanings given in the specification), which are known to be useful as herbicides, can be obtained in very good yields by reacting the corresponding 1-substituted-5(4H)-tetrazolinones with the corresponding carbamoyl chlorides in the presence of 4-dimethylaminopyridine.
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- Caffeic acid derivatives and pharmaceutical compositions containing the same
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Described are caffeic acid derivatives represented by the following formula: STR1 wherein either one of R1 and R2 is a hydrogen atom, a C1 -C6 alkyl group, a group --CO2 R4, or a group --CONR5 R6, R4, R5 and R6 being either a hydrogen atom or a particular group, and the other is the group --CO2 R4 or the group --CONF5 R6, or R1 and R2 are coupled together to represent a 5-membered ring so formed, Y represents a particular group or atom, X represents a substituted or unsubstituted C6 -C10 aryl, C7 -C12 aralkyl, heterocyclic or heterocyclic ring-alkyl group, m and n stand for particular integers, and R3 represents a hydrogen atom, a hydroxyl group, a group --OCO2 R7, R7 being a hydrogen atom or a particular group, or a group --OCONR8 R9, R8 representing a C1 -C6 alkyl group and R9 representing a hydrogen atom or a C1 -C6 alkyl group, and pharmaceutically acceptable salts thereof. Therapeutic agents containing the derivatives or salts are effective for diseases of the circulatory system.
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- Carbamate ester prodrugs of dopaminergic compounds: Synthesis, stability, and bioconversion
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Various carbamic acid esters (CAE) of a new class of dopaminergic drugs, 5-substituted 8-chloro-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepines, were synthesized and evaluated as prodrug forms with the aim of protecting the parent phenols against first-pass metabolism following oral administration. Monosubstituted CAE were found to be highly unstable at pH 7.4 and 37 °C, the half-lives of hydrolysis being between 4 and 40 min. Plasma from various species catalyzed the hydrolysis of the carbamates. N,N-Disubstituted carbamates, on the other hand, were stable both in buffer and plasma solutions. They showed a very potent inhibition of butyrylcholinesterase (EC 3.1.1.8), but were less potent inhibitors of the specific erythrocyte acetylcholinesterase (EC 3.1.1.17). In vitro incubations of an N,N-dimethylsubstituted carbamate ester (10) with liver microsomes from mouse and rat showed an appreciable formation of the parent phenolic compound. This bioconversion is suggested to occur via an initial cytochrome P-450-catalyzed hydroxylation to give an N-hydroxymethyl derivative which spontaneously decomposes to the N-monomethylcarbamate. It is concluded that N,N-disubstituted carbamate esters may be potentially useful prodrugs for the 7-hydroxy-3-benzazepines, whereas N-monosubstituted carbamates appear to be too chemically and enzymatically labile.
- Hansen,Faarup,Bundgaard
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p. 793 - 798
(2007/10/02)
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- Propenyl Carboxamide Derivatives as Antagonists of Platelet Activating Factor
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A series of N- 3-substituted propenyl carboxamide derivatives bearing an unsaturated bicyclic moiety in the 3-position was prepared and evaluated for PAF (platelet activating factor) antagonist activity.These compounds represent conformationally constrained direct analogues of the corresponding potent 5-arylpentadienecarboxamides (5).Most of the new compounds were active in a PAF-binding assay employing whole, washed dog platelets as the receptor source and inhibited PAF-induced bronchoconstriction in guinea pigs after intravenous administration.However, oral activity in the PAF-induced bronchoconstriction model was highly sensitive to the nature and substitution of the bicyclic ring system.The most interesting compounds included -(1-butyl-6-methoxy-2-naphthyl)-N--2-propenamide (4b), -(3-butyl-6-methoxy-2-benzothiophene-yl)-N--2-propenamide (4k), and -(3-butyl-6-methoxy-1-methyl-2-indolyl)-N--2-propenamide (4l) which inhibited PAF-induced bronchoconstriction in guinea pigs with IC50s of 3.0-5.4 mg/kg, when the animals were challenged 2 h after drug treatment.They were also highly effective 6 h after a 50 mg/kg oral dose.This study supports the notion that the key remote aromatic ring present in the 5-arylpentadienecarboxamides (5) is preferentially coplanar with the diene system for good PAF antagonist activity.
- Guthrie, Robert W.,Kaplan, Gerald L.,Mennona, Francis A.,Tilley, Jefferson W.,Kierstead, Richard W.,et al.
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p. 2856 - 2864
(2007/10/02)
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- COBALT-MEDIATED REACTIONS. A NEW SYNTHETIC APPROACH TO β-, χ- and δ-LACTAMS
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Unsaturated carbamylcobalt salophens, e.g. (2), undergo homolytic cleavage (heating, sunlamp) producing carbamyl radicals , viz (4) which then undergo cyclisation, accompanied by trapping (with CoII or TEMPO) or dehydrocobaltation, leading to functionalised β-, χ-, and δ-lactams e.g. (3), (6), (8), (11), (13) and (16).
- Gill, G. Bryon,Pattenden, Gerald,Reynolds, Stephen J.
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p. 3229 - 3232
(2007/10/02)
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- Pesticidal cyclic malonylphosphonic diamides
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Novel pesticidally active cyclic malonylphosphonic diamides of the formula STR1 in which X represents O or S, R1 represents alkyl, alkenyl, alkinyl, cycloalkyl, aryl or heteroaryl, each of which can be optionally substituted, R2 represents hydrogen, alkyl, aryl or aralkyl, R3 represents hydrogen, alkyl, aryl or aralkyl, and R4 represents an acyl radical, or salts thereof, Many intermediates are new,
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- A CONVENIENT PREPARATION OF CERTAIN N,N-DIALKYLCARBAMOYL CHLORIDES
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Certain N,N-dialkylcarbamoyl chlorides (2) were prepared in moderate yields by the reaction of ethyl N,N-dialkylcarbamates (1) with phosphoryl chloride in boiling acetonitrile.
- Hoshino, Osamu,Saito, Keiji,Ishizaki, Miyuki,Umezawa, Bunsuke
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p. 1887 - 1892
(2007/10/02)
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- Mixed anhydrides of carbamic and hydroxamic acids
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A base precursor represented by the following general formula (A) or (B): STR1 wherein A1, A2, A5, A6, A7, and A8 each represents a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, an alkenyl group, an aralkyl group, an aryl group, a substituted aryl group, an acyl group, or a heterocyclic group, and A1 and A2 can combine to form a ring and two of A5, A6, A7, and A8 can combine to form a ring, A3 and A4 each represents a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, or an aralkyl group, and A3 and A4 can combine to form a ring or A3 and A4 can be a double bond forming an imino group from STR2 and X represents a nucleophilic group.
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- A deuterium isotope effect on the inhibition of gastric secretion by N,N-dimethyl-N'-[2-(diisopropylamino)ethyl]-N'-(4,6-dimethyl-2-pyridyl)ure a. Synthesis of metabolites
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The use of isotopic substitution to retard the oxidative metabolism of the gastric antisecretory agent N,N-dimethyl-N'-[2-(diisopropylamino)ethyl]-N'-(4,6-dimethyl-2-pyridyl)ure a (1) and improve its antisecretory potency was examined. The pyridine ring methyl hydrogens of 1 were replaced with either deuterium or fluorine. The hexadeuterated analogue was found to be ~2.1 times more potent than the protio form (1) as an inhibitor of gastric acid secretion stimulated by gastrin tetrapeptide. The hexafluoro analogue was 0.4 times as potent as 1. A useful pyridine ring synthesis was developed to prepare the metabolites of 1, (4-hydroxymethyl) and (6-hydroxymethyl), and the hexafluoro analogue. These syntheses involved the condensation of 1,3-diketones with an appropriately N-substituted amidinoacetate.
- Hoffman, Jacob M.,Habecker, Charles N.,Pietruszkiewicz, Adolph M.,Bolhofer, William A.,Cragoe, Edward J.,et al.
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p. 1650 - 1653
(2007/10/02)
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- Etude par resonance magnetique multinucleaire d'intermediaires reactionnels electrophiles. Partie 8. Action des acides de Lewis chlores COCl2, POCl3, (CH3)2N=CHCl+Cl- et Cl2 sur l'hexamethylphosphotriamide (HMPT)
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The structural study of the electrophilic intermediates obtained from carboxamides and chlorinated Lewis acids is extended to the phosphoric amides.The action of COCl2 and POCl3 on hexamethylphosphotriamide (HMPT) can lead to a chlorophosphonium salt (3a) the structure of which is proved by nmr spectroscopy (1H, 13C, 31P, 15N).The mechanism of formation is comparable to that of the chloroiminium chloride (Vilsmeyer reagent) from the corresponding amides.The action of chlorine on HMPT does not lead to a stable salt of the same kind but essentially to the substitution product(2).A new biphosphorylated compound (6) has been identified when an excess of chlorine is reacted with HMPT.
- Poignant, S.,Gauvreau, J.R.,Martin, G.J.
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p. 946 - 952
(2007/10/02)
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- Process for the preparation of chloroformic acid aryl esters and cyclic carbonates
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A process for the preparation of chloroformic acid aryl-esters and cyclic carbonates of aryl compounds containing at least two phenolic hydroxy groups wherein aromatic compounds containing one or more hydroxy groups linked to an aromatic nucleus, are reacted with phosgene in the presence of catalytic amounts of N,N-disubstituted acid amide either under pressure or without pressure while removing the hydrogen chloride continuously from the reaction mixture. This improved process results in almost quantitative or very high yields of pure products and avoids problems such as disposal of waste water.
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- Optical brightening agents of naphthalimide derivatives
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A naphthalimide derivative having the formula STR1 wherein R is an alkyl, or cycloalkyl, an aralkyl, a haloalkyl, an alkoxyalkyl, a hydroxyalkyl, an N,N-dialkylaminoalkyl, an unsubstituted or halogen-, alkyl-, alkoxy- or hydroxy-substituted aryl, or an ammoniumalkyl; X is a group of the formula, STR2 wherein A is STR3 or an unsubstituted or halogen-substituted arylene, or a group of the formula, STR4 wherein R1 is hydrogen, an alkyl, phenyl, a hydroxyalkyl, or an alkoxyalkyl; Y is --CO--, --COO--, --CONR3 -- (where R3 is hydrogen or an alkyl), or --SO2 --; R2 is hydrogen, an alkyl, a cycloalkyl, an aralkyl, a haloalkyl, an alkyl- or aryl-substituted amino-alkyl, an unsubstituted or halogen-, alkyl-, alkoxy-, hydroxy-, amino- or alkylamino-substituted aryl, a group of the formula, STR5 (where R, R1 and Y are as defined above and R4 is a bivalent group), or a group of the formula, (where R5 is direct linkage or a bivalent group; Q+ is a substituted ammonium, a cycloammonium or a hydrazinium; and α- is an anion), Which is useful for optically brightening an organic polymer material.
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