- First synthesis of racemic trans propargylamino-donepezil, a pleiotrope agent able to both inhibit AChE and MAO-B, with potential interest against Alzheimer’s disease
-
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease towards which pleiotropic approach using Multi-Target Directed Ligands is nowadays recognized as probably convenient. Among the numerous targets which are today validated against AD, acetylcholinesterase (ACh) and Monoamine Oxidase-B (MAO-B) appear as particularly convincing, especially if displayed by a sole agent such as ladostigil, currently in clinical trial in AD. Considering these results, we wanted to take benefit of the structural analogy lying in donepezil (DPZ) and rasagiline, two indane derivatives marketed as AChE and MAO-B inhibitors, respectively, and to propose the synthesis and the preliminary in vitro biological characterization of a structural compromise between these two compounds, we called propargylaminodonepezil (PADPZ). The synthesis of racemic trans PADPZ was achieved and its biological evaluation established its inhibitory activities towards both (h)AChE (IC50 = 0.4 μM) and (h)MAO-B (IC50 = 6.4 μM).
- Guieu, Benjamin,Lecoutey, Cedric,Legay, Rémi,Davis, Audrey,De Oliveira Santos, Jana Sopkova,Altomare, Cosimo Damiano,Catto, Marco,Rochais, Christophe,Dallemagne, Patrick
-
-
- Novel 1,2,4-oxadiazole derivatives as selective butyrylcholinesterase inhibitors: Design, synthesis, and biological evaluation
-
Alzheimer’s disease (AD) is a progressive mental disorder that brings a huge economic burden to the healthcare systems. During this illness, acetylcholine levels in the cholinergic systems gradually diminish, which results in severe memory loss and cognitive impairments. Moreover, Butyrylcholinesterase (BuChE) enzyme participates in cholinergic neurotransmission regulation by playing a prominent role in the latter phase of AD. In this study, based on donepezil, which is an effective acetylcholinesterase (AChE) inhibitor, a series of 1,2,4-oxadiazole compounds were designed, synthesized and their inhibitory activities towards AChE and BuChE enzymes were evaluated. Some structures exhibited a higher selectivity rate towards BuChE in comparison to donepezil. Notably, compound 6n with an IC50 value of 5.07 μM and an SI ratio greater than 19.72 showed the highest potency and selectivity towards BuChE enzyme. The docking result revealed that compound 6n properly fitted the active site pocket of BuChE enzyme, and formed desirable lipophilic interactions and hydrogen bonds. Moreover, according to in silico ADME studies, these compounds have proper potential for being developed as new oral anti-Alzheimer’s agents.
- Akbarzadeh, Tahmineh,Hariri, Roshanak,Nazari, Maryam,Rezaee, Elham,Tabatabai, Sayyed Abbas
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p. 907 - 921
(2021/06/09)
-
- Fast continuous alcohol amination employing a hydrogen borrowing protocol
-
A continuous flow method for the direct conversion of alcohols to amines via a hydrogen borrowing approach is reported. The method utilises a low loading (0.5%) of a commercial catalyst system ([Ru(p-cymene)Cl2]2 and DPEPhos), reagent grade solvent and is selective for primary alcohols. Successful methylation of amines using methanol and the direct dimethylamination of alcohols using commercial dimethylamine solution are reported. The synthesis of two pharmaceutical agents Piribedil (5) and Buspirone (25) were accomplished in good yields employing these new methods.
- Labes, Ricardo,Mateos, Carlos,Battilocchio, Claudio,Chen, Yiding,Dingwall, Paul,Cumming, Graham R.,Rincón, Juan A.,Nieves-Remacha, Maria José,Ley, Steven V.
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supporting information
p. 59 - 63
(2019/01/11)
-
- Basic Anion-Exchange Resin-Catalyzed Aldol Condensation of Aromatic Ketones with Aldehydes in Continuous Flow
-
A general method for the aldol condensation of aromatic ketones with aldehydes was developed under continuous-flow conditions using a commercially available, strongly basic anion-exchange resin (A26) as catalyst. This procedure, in addition to exhibiting a wide substrate scope, promoted carbon-carbon bond formation under mild conditions using a quasi-stoichiometric ratio of starting reagents with good to excellent yields, thereby forming a limited amount of waste and allowing the process to be applied to sequential-flow systems. A proof of concept was developed in the first fully heterogeneously catalyzed two-step flow synthesis of donepezil, which is a blockbuster commercial anti-Alzheimer's drug.
- Laroche, Benjamin,Saito, Yuki,Ishitani, Haruro,Kobayashi, Shū
-
supporting information
p. 961 - 967
(2019/05/02)
-
- Novel N-benzylpiperidine carboxamide derivatives as potential cholinesterase inhibitors for the treatment of Alzheimer's disease
-
A series of fifteen acetylcholinesterase inhibitors were designed and synthesised based upon the previously identified lead compound 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl 1-benzylpiperidine-4-carboxylate (5) which showed good inhibitory activity (IC50 0.03 ± 0.07 μM) against acetylcholinesterase. A series of compounds were prepared wherein the ester linker in the original lead compound was exchanged for a more metabolically stable amide linker and the indanone moiety was exchanged for a range of aryl and aromatic heterocycles. The two most active analogues 1-benzyl-N-(5,6-dimethoxy-8H-indeno[1,2-d]thiazol-2-yl)piperidine-4-carboxamide (28) and 1-benzyl-N-(1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) piperidine-4-carboxamide (20) afforded in vitro IC50 values of 0.41 ± 1.25 and 5.94 ± 1.08 μM, respectively. In silico screening predicts that 20 will be a blood brain-barrier permeant, and molecular dynamic simulations are indicative of a close correlation between the binding of 20 and the Food and Drug Administration-approved cholinesterase inhibitor donepezil (1).
- van Greunen, Divan G.,Johan van der Westhuizen,Cordier, Werner,Nell,Stander,Steenkamp, Vanessa,Panayides, Jenny-Lee,Riley, Darren L.
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p. 680 - 693
(2019/07/09)
-
- Synthesis, bioactivity and molecular modeling studies on potential anti-Alzheimer piperidinehydrazide-hydrazones
-
A group of N-benzylpiperidine-3/4-carbohydrazide-hydrazones were designed, synthesized and evaluated for acetylcholinesterase (AChE), butyrylcholinesterase (BuChE)activities, Aβ42 self-aggregation inhibitory potentials, and antioxidant capacities, in vitro. All of the compounds displayed eeAChE and huAChE inhibitory activity in a range of IC50 = 5.68–11.35 μM and IC50 = 8.80–74.40 μM, respectively and most of the compounds exhibited good to moderate inhibitory activity on BuChE enzyme. Kinetic analysis and molecular modeling studies were also performed for the most potent compounds (1g and 1j). Not only the molecular modeling studies but also the kinetic analysis suggested that these compounds might be able to interact with the catalytic active site (CAS)and the peripheral anionic site (PAS)of the enzymes. In the light of the results, compound 1g and compound 1j may be suggested as lead compounds for multifunctional therapy of AD.
- Parlar, Sulunay,Sayar, Gozde,Tarikogullari, Ayse Hande,Karadagli, Sumru Sozer,Alptuzun, Vildan,Erciyas, Ercin,Holzgrabe, Ulrike
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p. 888 - 900
(2018/12/11)
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- Direct Reductive Amination of Carbonyl Compounds with H2 Using Heterogeneous Catalysts in Continuous Flow as an Alternative to N-Alkylation with Alkyl Halides
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A general continuous-flow procedure for direct reductive amination of secondary and primary amines with aromatic and aliphatic aldehydes as well as ketones is reported. The use of hydrogen gas and commercially available Pt/C as a heterogeneous catalyst is a key. In addition to exhibiting an excellent functional group tolerance, this method allows the fast formation of C?N bonds without production of any hazardous chemical waste. Applications to the synthesis of key intermediates toward active pharmaceutical ingredients (Donepezil and Arformoterol/Tamsulosin) are also described. (Figure presented.).
- Laroche, Benjamin,Ishitani, Haruro,Kobayashi, Shū
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supporting information
p. 4699 - 4704
(2018/12/04)
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- 4,5-dimethoxy-2-nitrobenzohydrazides and 1-(1-benzylpiperidin-4-yl)ethan-1-ones as potential antioxidant/cholinergic endowed small molecule leads
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The objective of this research is to generate leads for developing our ultimate poly-active molecules with utility in central nervous system (CNS) diseases. Indeed, poly-active molecules capable of mitigating brain free radical damage while enhancing acetylcholine signaling (via cholinesterase inhibition) are still being sought for combating Alzheimer’s disease (AD). We differentiate “poly-active” agents from “multi-target” ones by defining them as single molecular entities designed to target only specific contributory synergistic pharmacologies in a disease. For instance, in AD, free radicals either initiate or act in synergy with other pharmacologies, leading to disease worsening. For this preliminary report, a total of 14 (i.e., 4,5-dimethoxy-2-nitrobenzohydrazide plus 1-(1-benzylpiperidin-4-yl)ethan-1-one) derivatives were synthesized and screened, in silico and in vitro, for their ability to scavenge free radicals and inhibit acetylcholinesterase (AChE)/butyrylcholinesterase (BuChE) enzymes. Overall, six derivatives (4a, 4d, 4e, 4f, 4g, 9b) exhibited potent (>30%) antioxidant properties in the oxygen radical absorbance capacity (ORAC) assay. The antioxidant values were either comparable or more potent than the comparator molecules (ascorbic acid, resveratrol, and trolox). Only three compounds (4d, 9a, 9c) yielded modest AChE/BuChE inhibitions (>10%). Please note that a SciFinder substance data base search confirmed that most of the compounds reported herein are new, except 9a and 9c which are also commercially available.
- Banu, Rukhsar,Gerding, Jason,Franklin, Cynthia,Sikazwe, Donald,Horton, William,T?r?k, Marianna,Davis, Julian,Cheng, Kwan H.,Nakazwe, Muziya,Mochona, Bereket
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- NOVEL MODULATORS OF THE 5-HYDROXYTRYPTAMINE RECEPTOR 7 AND THEIR METHOD OF USE
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Pharmaceutical compositions of the invention comprise functionalized lactone derivatives having a disease-modifying action in the treatment of diseases associated with dysregulation of 5-hydroxytryptamine receptor 7 activity.
- -
-
Paragraph 0388
(2018/06/06)
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- Mitsunobu Reaction Using Basic Amines as Pronucleophiles
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A novel protocol for extending the scope of the Mitsunobu reaction to include amine nucleophiles to form C-N bonds through the utilization of N-heterocyclic phosphine-butane (NHP-butane) has been developed. Both aliphatic alcohols and benzyl alcohols are suitable substrates for C-N bond construction. Various acidic nucleophiles such as benzoic acids, phenols, thiophenol, and secondary sulfonamide also provide the desired products of esters, ethers, thioether, and tertiary sulfonamide with 43-93% yields. Importantly, C-N bond-containing pharmaceuticals, Piribedil and Cinnarizine, have been synthesized in one step from the commercial amines under this Mitsunobu reaction system.
- Huang, Hai,Kang, Jun Yong
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p. 6604 - 6614
(2017/07/15)
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- Oxidation-Reduction Condensation of Diazaphosphites for Carbon-Heteroatom Bond Formation Based on Mitsunobu Mechanism
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An efficient oxidation-reduction condensation reaction of diazaphosphites with various nonacidic pronucleophiles in the presence of DIAD as a weak oxidant has been developed for carbon-heteroatom bond formation. This mild process affords structurally diverse tertiary amines, secondary amines, esters, ethers, and thioethers in moderate to excellent yields. The selective synthesis of secondary amines from primary amines has been achieved. Importantly, a practical application to the synthesis of antiparkinsonian agent piribedil has been demonstrated.
- Huang, Hai,Kang, Jun Yong
-
supporting information
p. 544 - 547
(2017/02/10)
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- Industrially scalable synthesis of anti-alzheimer drug donepezil
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This paper describes a simple, efficient and industrially scalable total synthesis of donepezil hydrochloride. The article also reported the X-ray studies of the 2-(1-benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-1-one, an intermediate in the synthesis of donepezil. The crystal structure analysis of 2-(1-benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-1-one shows that it crystallizes in monoclinic class under the space group P121/c1 with cell parameters, a = 17.2992(7) ?, b = 10.1999(4) ?, c = 11.9539(5) ?, β = 103.450(2)°, V = 2051.42(15) ?3 and Z = 4.
- Gaonkar, Santosh L.,Nadaf,Bilehal, Dinesh,Shetty, Nitinkumar S.
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p. 1999 - 2004
(2017/07/27)
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- Preparation method of 1-benzyl-4-piperidine formaldehyde
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The invention discloses a preparation method of 1-benzyl-4-piperidine formaldehyde. The preparation method comprises the following steps of carrying out a partial reduction reaction on 1-benzyl-4-piperidine methyl formate or 1-benzyl-4-piperidine ethyl formate and a vitride complex in a solvent; then collecting the 1-benzyl-4-piperidine formaldehyde from a reaction product. According to the preparation method of the 1-benzyl-4-piperidine formaldehyde, disclosed by the invention, 1-benzyl-4-piperidine formic acid esters are used as raw materials, the vitride complex is used as a reducing agent, the raw materials are easy to prepare, the operation is simple and convenient, the yield is high, the product purity is good, and the preparation method is suitable for industrial production.
- -
-
Paragraph 0044; 0045; 0046; 0047
(2016/10/08)
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- A simple iridicycle catalyst for efficient transfer hydrogenation of n-heterocycles in water
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A cyclometalated iridium complex is shown to catalyse the transfer hydrogenation of various nitrogen heterocycles, including but not limited to quinolines, isoquinolines, indoles and pyridinium salts, in an aqueous solution of HCO2H/HCO2Na under mild conditions. The catalyst shows excellent functional-group compatibility and high turnover number (up to 7500), with catalyst loadings as low as 0.01 mol % being feasible. Mechanistic investigation of the quinoline reduction suggests that the transfer hydrogenation proceeds via both 1,2- and 1,4-addition pathways, with the catalytic turnover being limited by the step of hydride transfer. An easily accessible iridicycle catalyst effects the transfer hydrogenation of a wide variety of N-heterocycles in water, including quinolines, isoquinolines, indoles, quinoxalines, and pyridines. The catalyst shows excellent functional-group compatibility and high turnover number (up to 7500), even with low catalyst loadings.
- Talwar, Dinesh,Li, Ho Yin,Durham, Emma,Xiao, Jianliang
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supporting information
p. 5370 - 5379
(2015/03/30)
-
- Part I: The development of the catalytic wittig reaction
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We have developed the first catalytic (in phosphane) Wittig reaction (CWR). The utilization of an organosilane was pivotal for success as it allowed for the chemoselective reduction of a phosphane oxide. Protocol optimization evaluated the phosphane oxide precatalyst structure, loading, organosilane, temperature, solvent, and base. These studies demonstrated that to maintain viable catalytic performance it was necessary to employ cyclic phosphane oxide precatalysts of type 1. Initial substrate studies utilized sodium carbonate as a base, and further experimentation identified N,N-diisopropylethylamine (DIPEA) as a soluble alternative. The use of DIPEA improved the ease of use, broadened the substrate scope, and decreased the precatalyst loading. The optimized protocols were compatible with alkyl, aryl, and heterocyclic (furyl, indolyl, pyridyl, pyrrolyl, and thienyl) aldehydes to produce both di- and trisubstituted olefins in moderate-to-high yields (60-96 %) by using a precatalyst loading of 4-10 mol %. Kinetic E/Z selectivity was generally 66:34; complete E selectivity for disubstituted α,β-unsaturated products was achieved through a phosphane-mediated isomerization event. The CWR was applied to the synthesis of 54, a known precursor to the anti-Alzheimer drug donepezil hydrochloride, on a multigram scale (12.2 g, 74 % yield). In addition, to our knowledge, the described CWR is the only transition-/heavy-metal-free catalytic olefination process, excluding proton-catalyzed elimination reactions. A point of difference: By utilizing an organosilane to chemoselectively reduce a phosphane oxide precatalyst to a phosphane (see scheme), the first catalytic (in phosphane) Wittig reaction has been developed. The methodology has been applied to the synthesis of 22 disubstituted and 24 trisubstituted olefins, including a multigram synthesis of a precursor to the anti-Alzheimer drug donepezil hydrochloride.
- O'Brien, Christopher J.,Nixon, Zachary S.,Holohan, Andrew J.,Kunkel, Stephen R.,Tellez, Jennifer L.,Doonan, Bryan J.,Coyle, Emma E.,Lavigne, Florie,Kang, Lauren J.,Przeworski, Katherine C.
-
supporting information
p. 15281 - 15289
(2013/11/06)
-
- Use of structure based design to increase selectivity of pyridyl-cinnoline phosphodiesterase 10A (PDE10A) inhibitors against phosphodiesterase 3 (PDE3)
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We report our successful effort to increase the PDE3 selectivity of PDE10A inhibitor pyridyl cinnoline 1 using a combination of computational modeling and structural-activity relationship investigations. An analysis of the PDE3 catalytic domain compared to the co-crystal structure of cinnoline analog 1 in PDE10A revealed two areas of structural differences in the active sites and suggested areas on the scaffold that could be modified to exploit those unique structural features. Once SAR established the cinnoline as the optimal scaffold, modifications on the methoxy groups of the cinnoline and the methyl group on the pyridine led to the discovery of compounds 33 and 36. Both compounds achieved significant improvement in selectivity against PDE3 while maintaining their PDE10A inhibitory activity and in vivo metabolic stability comparable to 1.
- Hu, Essa,Kunz, Roxanne K.,Rumfelt, Shannon,Hitchcock, Stephen A.,Lindstrom, Michelle,Treanor, James,Andrews, Kristin L.,Li, Chun
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p. 6938 - 6942,5
(2020/09/02)
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- LACTAM ACETAMIDES AS CALCIUM CHANNEL BLOCKERS
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The present application relates to calcium channel inhibitors containing compounds of formula (I) wherein Ar1, n, R1, X and Y are as defined in the specification. The present application also relates to compositions comprising such compounds, and methods of treating conditions and disorders using such compounds and compositions.
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Page/Page column 19-20
(2011/10/10)
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- COMPOUND WITH SEROTONINERGIC ACTIVITY, PROCESS FOR PREPARING IT AND PHARMACEUTICAL COMPOSITION COMPRISING IT
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Compound of formula (I) in which R1, R2 and R3 are defined in the following description, and the pharmaceutically acceptable acid-addition or base-addition salts thereof. The invention also relates to a process and an intermediate for preparing it, and to a pharmaceutical composition comprising it. The invention also relates to the use of a novel 2H-pyrrolo[3,4-c]quinoline compound for preparing a pharmaceutical composition that is active in the treatment of disturbances of the serotoninergic system.
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Page/Page column 28
(2010/04/03)
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- The design and discovery of novel amide CCR5 antagonists
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The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SAR's which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential.
- Pryde, David C.,Corless, Martin,Fenwick, David R.,Mason, Helen J.,Stammen, Blanda C.,Stephenson, Peter T.,Ellis, David,Bachelor, David,Gordon, David,Barber, Christopher G.,Wood, Anthony,Middleton, Donald S.,Blakemore, David C.,Parsons, Gemma C.,Eastwood, Rachel,Platts, Michelle Y.,Statham, Keith,Paradowski, Kerry A.,Burt, Catherine,Klute, Wolfgang
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supporting information; scheme or table
p. 1084 - 1088
(2009/08/07)
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- SUBSTITUTED ARYL-FUSED SPIROCYCLIC AMINES
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Substituted Aryl-fused Spirocyclic Amines of the formula (I): are provided, as are methods for their preparation and use. Such compounds may generally be used to modulate ligand binding to histamine H3 receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of disorders in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and therapeutic methods are provided, as are methods for using such ligands for detecting histamine H3 receptors (e.g., receptor localization studies).
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Page/Page column 36
(2009/04/25)
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- PHOSPHODIESTERASE 10 INHIBITORS
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The present invention is directed to certain compounds useful as phosphodiesterase 10 (PDE10) inhibitors that have the formula where R1, R2, R3, R4, X, Y and Z are as defined herein, pharmaceutical compositions containing such compounds and processes for preparing such compounds. The invention is also directed to methods of treating diseases mediated by PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, and the like.
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Page/Page column 14
(2009/04/24)
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- PHOSPHODIESTERASE 10 INHIBITORS
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The present invention is directed to compounds, useful as PDE10 inhibitors, having the formula where R1,R2, R3, R4, X, Y and z are as defined herein, pharmaceutical compositions containing such compounds. and processes for preparing such compounds. The invention is also directed to methods of treating diseases mediated by PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, and the like
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Page/Page column 13
(2009/04/24)
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- Highly chemoselective metal-free reduction of tertiary amides
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This communication describes the chemoselective metal-free reduction of tertiary amides to the corresponding amines. Hantzsch ester is used as a mild reducing agent for the reduction of trifluoromethanesulfonic anhydride activated amides providing the tertiary amines with high functional group tolerance. Copyright
- Barbe, Guillaume,Charette, Andre B.
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-
- An improved and efficient process for the production of donepezil hydrochloride: Substitution of sodium hydroxide for n-butyl lithium via phase transfer catalysis
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A simple, efficient and highly economic process for the production of donepezil hydrochloride (1), an anti-Alzheimer drug is reported. The process relies upon improved and large-scale synthesis of a key intermediate: 1-benzylpiperidine-4-carboxaldehyde (2), and the introduction of operationally simple chemistry at the penultimate stage wherein 2 is reacted with 5,6-dimethoxy indanone (3) in the presence of sodium hydroxide and a phase transfer catalyst (PTC) in a biphasic solvent to furnish the intermediate 4, which is reduced and directly treated with hydrochloric acid to furnish highly pure donepezil hydrochloride with desired polymorphic form. The improved process provides donepezil hydrochloride at considerably lower cost and allows the omission of hazardous chemicals.
- Niphade, Navanath,Mali, Anil,Jagtap, Kunal,Ojha, Ramesh Chandra,Vankawala, Pravinchandra J.,Mathad, Vijayavitthal T.
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p. 731 - 735
(2013/01/03)
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- 5-HTX MODULATORS
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This invention relates to compounds which bind to serotonin receptors inside or outside the central nervous system, in particular compounds which bind to the 5-HT2 or 5-HT7 receptors, their preparation and use, compositions containing them, and methods of treatment using them.
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Page/Page column 32-33
(2008/06/13)
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- PESTICIDAL SUBSTITUTED PIPERIDINES
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The invention relates to the use of piperidine derivatives encompassed from the general formula (I) for the control of pests, including arthropods and helminths, and a method for the control of pests.
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Page/Page column 51; 104
(2008/06/13)
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- PHARMACEUTICAL COMPOUNDS
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Fused pyrimidines of formula (I); wherein A represents a thiophene or furan ring; n is 1 or 2; R1 is a group of formula (II); wherein m is 0 or 1; R30 is H or C1-C6 alkyl; R4 and R5 form, together with the N atom to which they are attached, a 5- or 6-membered saturated N-containing heterocyclic group which includes 0 or 1 additional heteroatoms selected from N, S and O, which may be fused to a benzene ring and which is unsubstituted or substituted; or one of R4 and R5 is alkyl and the other is a 5- or 6-membered saturated N-containing heterocyclic group as defined above or an alkyl group which is substituted by a 5- or 6-membered saturated N-containing heterocyclic group as defined above; R2 is selected from formula (a); wherein R6 and R7 form, together with the nitrogen atom to which they are attached, a morpholine, thiomorpholine, piperidine, piperazine, oxazepane or thiazepane group which is unsubstituted or substituted; and formula (b); wherein Y is a C2-C4 alkylene chain which contains, between constituent carbon atoms of the chain and/or at one or both ends of the chain, 1 or 2 heteroatoms selected from O, N and S, and which is unsubstituted or substituted; and R3 is an indazole group which is unsubstituted or substituted; and the pharmaceutically acceptable salt thereof have activity as inhibitors of P13K and may thus be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour associated with P13 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorders and neurological disorders. Processes for synthesizing the compounds are also described.
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Page/Page column 69-70
(2008/06/13)
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- FUSED BENZENE DERIVATIVE AND USE
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The present invention provides a compound represented by the general formula: [wherein Ring A represents an optionally substituted 5- to 8-membered ring, Ring B represents a further optionally substituted 4- to 10-membered ring, Ring C represents a further optionally substituted benzene ring, X1 represents carbon atom, X2 represents a carbon atom, an oxygen atom, etc., W represents a nitrogen atom, etc., Y11 represents a group represented by the formula CR2R3' (wherein R2 represents a hydrogen atom, a cyano group, a nitro group, etc., and R3' represents a hydrogen atom, a cyano group, a nitro group, etc., respectively), Y21 represents a group represented by the formula CR4R5' (wherein R4 represents a hydrogen atom, a cyano group, a nitro group, etc., and R5' represents a hydrogen atom, a cyano group, a nitro group, etc., respectively), etc., and R1 represents an electron-withdrawing group, respectively. The formula represents a single bond or a double bond] or a salt thereof, which is useful as an androgen receptor modulator.
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Page/Page column 48
(2010/02/12)
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- Design, synthesis, and preliminary pharmacological evaluation of a set of small molecules that directly activate Gi proteins
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Heterotrimeric G proteins play a pivotal role in the communication of cells with the environment. G proteins are stimulated by cell surface receptors (GPCR) that catalyze the exchange of GDP, bound to Gα subunit, with GTP and can per se be the target of drugs. Based on the structure of two nonpeptidic modulators of Gi proteins, a series of new molecules characterized by a long hydrophobic chain and at least two nitrogen atoms protonated at physiological pH was designed. The compounds were tested for their ability to stimulate binding of GTPγS to recombinant Gi proteins. Gi activation properties were also evaluated by inhibition of adenylyl cyclase activity in intact lymphocytes. Most compounds were able to stimulate GTPγS binding and to inhibit cAMP production at micromolar doses. Among the active compounds, 34 showed good efficacy and was the most potent compound studied, particularly on αo subtype; its regioisomer, 36, was the most efficacious one. Compound 7 showed also an interesting profile as it showed selectivity toward the αo subtype, in both efficacy and potency. Some of the compounds synthesized and found to be active may be useful leads to develop more potent and selective Gi protein modulators.
- Manetti, Dina,Mannelli, Lorenzo Di Cesare,Dei, Silvia,Galeotti, Nicoletta,Ghelardini, Carla,Romanelli, Maria Novella,Scapecchi, Serena,Teodori, Elisabetta,Pacini, Alessandra,Bartolini, Alessandro,Gualtieri, Fulvio
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p. 6491 - 6503
(2007/10/03)
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- BENZAMIDE DERIVATIVES
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A compound represented by formula (1): wherein X is a single bond or a substituted or unsubstituted lower alkylene group; Z is a saturated or unsaturated monocyclic hydrocarbon ring group or the like; and each of R1, R2, R3 and R4, which may be the same or different, is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a carboxyl group, a substituted or unsubstituted alkyl group, or the like, a prodrug of said compound, or a pharmaceutically acceptable salt of said compound or prodrug has inhibitory effect on Rho kinase and hence is useful for treating diseases which are such that morbidity due to them is expected to be improved by inhibition of Rho kinase and secondary effects such as inhibition of the Na+/H+ exchange transport system caused by the Rho kinase inhibition, for example, hypertension.
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-
-
- Anthranyl amides and their use as medicaments
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Substituted anthranilamides and use thereof as pharmaceutical agents for treating diseases that are triggered by persistent angiogenesis as well as their intermediate products for the production of anthranilamides are described.
- -
-
-
- Method for preparing alpha-sulfonyl hydroxamic acid derivatives
-
Compounds of the formula: that can be important as matrix metalloproteinase (MMP) and TNF-alpha converting enzyme (TACE) inhibitors, phosphodiesterase inhibitors, renin inhibitors, antithrombotics, and 5-lipoxygenase inhibitors are prepared by novel methods of the present invention.
- -
-
-
- Large scale synthesis of N-benzyl-4-formylpiperidine through partial reduction of esters using aluminum hydride reagents modified with pyrrolidine
-
The modification of sodium bis(2-methoxyethoxy)aluminum hydride (SMEAH) with pyrrolidine provided a highly selective reducing agent to transform N-benzyl-4-ethoxycarbonylpiperidine into N-benzyl-4-formylpiperidine 1 under mild conditions. However, this simple modification led to a significant amount of N-benzyl-4-(pyrrolidin-1-ylmethyl)piperidine 4 due to overreduction of an intermediate. Our extensive research revealed that an alkaline base such as potassium tert-butoxide could suppress the formation of the by-product to give the desired aldehyde, enabling us to establish a viable synthetic process for a key intermediate of donepezil hydrochloride. The potential applications of this reagent are also described.
- Abe,Haga,Negi,Morita,Takayanagi,Hamamura
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p. 2701 - 2710
(2007/10/03)
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- Synthesis and preliminary pharmacological results on new naphthalene derivatives as 5-HT4 receptor ligands
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The indole derivative GR 113808 is currently used as the reference ligand for labelling the 5-HT4 serotoninergic receptors. Previous works in our laboratories established the bioisosteric equivalency of the indole heterocycle and naphthalene in a series of melatonin receptor ligands. Based on this knowledge we designed new analogues of GR 113808 by introducing two bioisosteric modifications: firstly, the indole ring was replaced by a naphthalene one and secondly, the ester linkage was replaced by an amide group. Compound 8 emerged within this novel series as it displayed high and selective affinity at 5-HT4 receptors (Ki 5-HT4 = 6 nM, Ki 5-HT3 = 100 nM, Ki values at other 5-HT receptors were higher than 1 000 nM). Compound 8 is currently undergoing further pharmacological evaluation. (C) 2000 Editions scientifiques et medicales Elsevier SAS.
- Diouf, Ousmane,Depreux, Patrick,Chavatte, Philippe,Poupaert, Jacques Henri
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p. 699 - 706
(2007/10/03)
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- Benzyl-piperidine derivatives
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Benzly-piperidine derivatives of formula I and their pharmaceutically acceptable salts are used in the control of psychotic disorders which are caused by damage to the dopamine system, especially schizophrenia. STR1 A is STR2 B is STR3 R 1, R 2 and R 3 are independently hydrogen, amino, nitro, halogen, lower-alkly or lower-alkoxy. R 4, R 5 and R 6 are independently hydrogen, nitro, halogen, lower-alkyl, lower-alkoxy, cyano, trifluoromethyl, amino, lower-alkylamino or di-lower-alkylamino. R 7, R 2 and R 9 are independently hydrogen, amino or nitro.
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- 112. Novel heterospirocyclic 3-amino-2H-azirines as synthons for heterocyclic α-amino acids)
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The heterospirocyclic N-methyl-N-phenyl-2H-azirin-3-amines (3-(N- methyl-N-phenylamino)-2H-azirines) 1a-d with a tetrahydro-2H-pyran, tetrahydro-2H-thiopyran, and a N-protected piperidine ring respectively, were synthesized from the corresponding heterocyclic 4-carboxamides 2 by consecutive treatment with lithium diisopropylamide (LDA), diphenyl phosphorochloridate (DPPCl), and sodium azide (Scheme 4). The reaction of these aminoazirines with thiobenzoic acid in CH2Cl2 at room temperature gave the thiocarbamoyl-substituted benzamides 13a-d in high yield. The azirines 1a-d were used as synthons for heterocyclic α-amino acids in the preparation of tripeptides of the type Z-Aib-Xaa-Aib-N(Ph)Me (18) by following the protocol of the 'azirine/ox-azolone method': treatment of Z- Aib with 1 to give the dipeptide amide 15, followed by selective hydrolysis to the corresponding acid 16 and coupling with the 2,2-dimethyl-2H-azirin-3- amine 17 gave 18, again in high yield (Scheme 5). With some selected examples of 18, the selective deprotection of the amino and the carboxy group, respectively, was demonstrated (Scheme 6). The solid-state conformations of the protected tripeptides 18a-d, as well as that of the corresponding carbocyclic analogue 18e, were determined by X-ray crystallography (Figs. 1- 3 and Tables 1-3). All five tripeprides adopt a β-turn conformation of type III or III. The solvent dependence of the chemical shifts of the NH resonances (Fig. 6) suggests that there is an intramolecular H-bond between H-N(4) and O(11) in all cases, which is an indication that a relatively rigid β-turn structure also persists in solution. Surprisingly, the tripeptide acid 20a shows no intramolecular H-bond in the crystalline state (Fig. 7); O(11) is involved in an intermolecular H-bond with the OH group of the carboxy function.
- Straessler, Christoph,Linden, Anthony,Heimgartner, Heinz
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p. 1528 - 1551
(2007/10/03)
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- Structure-activity relationship studies of novel 4-[2-[bis(4- fluorophenyl)methoxy]ethyl]-1-(3-phenylpropyl)piperidine analogs: Synthesis and biological evaluation at the dopamine and serotonin transporter sites
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Several analogs of the potent dopamine (DA) transporter ligand 4-[2- [bis(4-fluorophenyl)-methoxy]ethyl]-1-(3-phenylpropyl)piperidine, 1b, were made and biologically evaluated for their binding at the DA and serotonin (5HT) transporters in rat striatal membranes. Different alkyl chain lengths and substitutions were introduced in these molecules to generate an optimum activity and selectivity for the DA transporter. In general, unsubstituted and fluoro-substituted compounds were the most active and selective for the DA transporter. The compound 4-[2(diphenylmethoxy)ethyl]-1-benzylpiperidine, 9a, showed high potency and was the most selective for the DA transporter (5HT/DA = 49) in this series of compounds. Some of these novel analogs were found to be more selective in binding at the DA transporter than the original GBR 12909 molecule, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3- phenylpropyl)piperidine.
- Dutta,Xu,Reith
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p. 749 - 756
(2007/10/03)
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- TRICYCLIC-CYCLIC AMINES AS NOVEL CHOLINESTERASE INHIBITORS
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Compounds of the formula wherein ring A, ring B, ring D, R2, R3, R4 R5, R6, R11, R12, R13, E, G, X and P are as defined below. The compounds of formula I are cholinesterase inhibitors and are useful in enhancing memory in patients suffering from dementia and Alzheimer's disease.
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- Synthesis of a new series of 2,7-diazaspirononan-1-ones and study of their cholinergic properties
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A new series of substituted 2,7-diazaspirononan-1-ones (1a-l), structurally related to the muscarinic agonist RS-86, has been synthesized and tested for cholinergic properties both in vitro and in vivo.None of the compounds showed significant cholinergic properties at either the central or peripheral level.A possible explanation for the lack of activity is given.Alzheimer's disease / cholinergic system / RS-86 / muscarinic agonists
- Cignarella, G.,Villa, S.,Barlocco, D.
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p. 115 - 120
(2007/10/02)
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- ETHER DERIVATIVES OF ALKYL PIPERIDINES AND PYRROLIDINES AS ANTIPSYCHOTIC AGAENTS
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Novel unsaturated ether derivatives of alkyl piperidine and pyrrolidine compounds, pharmaceutical compositions containing them, methods of preparation and methods of using these compounds as antipsychotic agents are disclosed.
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- Synthesis and pharmacological evaluation of a new class of 2-oxo-8- azaspiro (4,5)decan-1-ones as analogues of the muscarinic agonist RS-86
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A new series of 8-substituted-2-oxo-8-azapsiro (4,5)decan-1-ones has been synthesized and compounds tested for their cholinergic properties in comparison with the muscarinic agonist RS-86. Preliminary in vitro and in vivo pharmacological data indicate that none of them is provided with significant cholinergic effects either at central or peripheral level. A possible explanation for the lack of activity is given on the basis of conformational studies.
- Cignarella,Villa,Barlocco
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p. 1439 - 1445
(2007/10/02)
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- Piperidine ether derivatives as psychotropic drugs or plant fungicides
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There are provided piperidine ether derivatives, pharmaceutical and agricultural compositions containing them useful for treating physiological or drug induced psychosis or dyskinesia in a mammal or fungal disease in plants. Also provided are methods for preparing these compounds.
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- Novel piperidine σ receptor ligands as potential antipsychotic drugs
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σ receptor ligands represent a new class of potential antipsychotic drugs. This paper presents the structure-activity relationships leading to novel disubstituted piperidine σ ligands, which have little or no affinity for dopamine D2 receptors. Selectivity for σ sites over dopamine D2 or serotonin 5-HT2 receptors appears to be governed by the chemical nature of the piperidine nitrogen substituent, its distance from the basic nitrogen, and its orientation relative to the other piperidine substituent. Several of these compounds have good oral potency in some animal models used to evaluate potential antipsychotic drugs. The N-cyclopropylmethyl ketones and ethers (e.g. 6i (DuP 734), 6q, 18a, and 18n) have the best in vivo potency. Compounds 6i (DuP 734) and 6q did not cause catalepsy in the rat, even at very high doses. On the basis of the pharmacology profiles of these σ ligands, we propose these compounds may be effective antipsychotic drugs, which do not induce extrapyramidal side effects or tardive dyskinesia.
- Gilligan,Cain,Christos,Cook,Drummond,Johnson,Kergaye,McElroy,Rohrbach,Schmidt,Tam
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p. 4344 - 4361
(2007/10/02)
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- Substituent variation in azabicyclic triazole- and tetrazole-based muscarinic receptor ligands
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The effect of variation of the 1-azabicyclic substituent on the novel 1,2,3-triazol-4-yl-, 1,2,4-triazol-1-yl-, tetrazol-5-yl-, and tetrazol-2-yl- based muscarinic receptor ligands has been studied, and the exo- azabicyclic[2.2.1]hept-3-yl substituent was found to give the most potent and efficacious compounds. In addition, variation of the second substituent on 1,2,4-triazol-1-yl- and tetrazol-2-yl-based muscarinic receptor ligands has yielded a series of novel compounds with high potencies and efficacies, ranging from full agonists to antagonists. Small lipophilic electron withdrawing substituents give potent but low efficacy compounds, while small polar electron donating substituents give potent and efficacious compounds. The activity of these compounds is described in terms of a model of the receptor involving lipophilic and hydrogen bonding interactions. These compounds provide muscarinic ligands with high potency and a range of efficacies suitable for testing as candidate drugs in the treatment of Alzheimer's disease.
- Jenkins,Wadsworth,Bromidge,Orlek,Wyman,Riley,Hawkins
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p. 2392 - 2406
(2007/10/02)
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- Synthesis of nitrosourea derivatives of pyridine and piperidine as potential anticancer agents.
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Nitrosourea derivatives 18-22 which utilize either a piperidine or pyridine ring as a carrier group were synthesized and evaluated for anticancer activity. N'-(1-Benzyl-4-piperidinyl)-N-(2-chloroethyl)-N-nitosourea hydrogen maleate (19) exhibited good activity against intracranial L1210 leukemia as well as the mouse ependymoblastoma brain tumor system. Compound 19 exhibited comparable activity in the Lewis lung carcinoma system to N,N'-bis(2-chloroethyl)-N-nitrosourea. Replacement of the N-benzyl group in both the 3-piperidinyl- and 4-piperidinylnitrosoureas resulted in less active compounds in all tumor systems tested. The 3-pyridylnitrosourea 22 was inactive in the L-1210 leukemia system.
- Crider,Lamey,Floss,Cassady,Bradner
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p. 848 - 851
(2007/10/02)
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