- Optimization of bifunctional piperidinamide derivatives as σ1R Antagonists/MOR agonists for treating neuropathic pain
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Here, we describe the optimization, synthesis, and associated pharmacological analgesic activities of a new series of bifunctional piperidinamide derivatives as sigma-1 receptor (σ1R) antagonists and mu opioid receptor (MOR) agonists. The new compounds were evaluated in vitro in σ1R and MOR binding assays. The most promising compound 114 (also called HKC-126), showed superior affinities for σ1R and MOR and good selectivity to additional receptors related to pain. Compound 114 showed powerful dose-dependent analgesic effects in the acetic acid writhing test, formalin test, hot plate test, and chronic constriction injury (CCI) neuropathic pain model. In contrast to an equianalgesic dose of fentanyl, compound 114 produced fewer opioid-like side effects, such as reward liability, respiratory depression, physical dependence, and sedation. Lastly, the pharmacokinetic properties of this drug were also acceptable, and these results suggest that compound 114, as a mixed σ1R/MOR ligand, has potential for treating neuropathic pain.
- Chen, Yin,Hao, Chao,Liu, Bi-Feng,Liu, Xin,Ma, Ru,Ma, Yurong,Xiong, Jiaying,Xu, Junyi,Ye, Jiaqi,Zhang, Guisen,Zhang, Shuang,Zhuang, Tao
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- Regioselective Thermal [3+2]-Dipolar Cycloadditions of α-Diazoacetates with α-Sulfenyl/Sulfinyl/Sulfonyl-β-Chloroacrylamide Derivatives to Form Densely Functionalised Pyrazoles
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Highly regioselective synthetic methodology leading to densely functionalised C(3), C(4) and C(5) substituted pyrazoles 10a–q, 14a-i and 16a–g via thermal [3+2]-dipolar cycloaddition, of α-diazoacetates and α-thio-β-chloroacrylamides, at the sulfide, sulfoxide and sulfone levels of oxidation, is described. This method allows access to C(4)-sulfenyl or sulfonyl pyrazoles, through migration of the sulfur substituent at the sulfide and sulfone oxidation levels, while elimination of the sulfinyl group leading to 3,5-disubstituted pyrazoles, is observed. While the sulfide migration is readily rationalised, the carbon to carbon 1,2-sulfonyl migration is unprecedented and mechanistically intriguing. The synthetically versatile generation of densely functionalised pyrazoles containing substituents amenable to further modification offers advantages over alternative synthetic routes. Isolation of the N-alkylated pyrazoles 11a and 12a as by-products from the cycloaddition through further reaction of the pyrazoles 10 with excess α-diazoacetate, proved useful in rationalising the tautomeric behaviour evident in the NMR spectra of the pyrazoles, with the position of tautomeric equilibrium influenced by solvent and substituents.
- Flynn, Aaran J.,Ford, Alan,Khandavilli, U. B. Rao,Lawrence, Simon E.,Maguire, Anita R.
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supporting information
p. 5368 - 5384
(2019/06/24)
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- Dichloromethane as a chlorination reagent for α-bromocarbonyl compounds in the presence of a copper catalyst
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We found that dichloromethane is a powerful chlorinating reagent for the congested 3° and 2° Csp3Br bond of α-bromocarbonyl amides, esters, and ketones. In the presence of an appropriate copper complex as a catalyst, the desired chlorination occurred within an hour. Control experiments revealed that in situ-generated CuCl2 is a key chlorinating agent that reacts with the 3° or 2° alkyl radicals generated by the reaction between an α-bromocarbonyl compound and a Cu(I) salt.
- Takeuchi, Kentaro,Ishida, Syo,Nishikata, Takashi
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supporting information
p. 644 - 646
(2017/08/30)
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- Inhibitory Effects of New Mercapto Xanthine Derivatives in Human mcf7 and k562 Cancer Cell Lines
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A series of new 2-methyl-2-[(1,3-Diethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]-N- substituted arylacetamides were synthesized. The antitumor activity of these purine based compounds were evaluated on breast cancer (MCF7) and leukemic cancer (K562) cell lines via cell viability assay utilizing the tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). These results were substantiated using computer docking experiments (LigandFit docking engine and PMF scoring function) which predict that the antitumor activity of these new compounds may be attributable to their abilities to effectively bind and block oncogenic tyrosine kinases, particularly bcr/abl.
- Sultani, Haider N.,Ghazal, Rasha A.,Hayallah, Alaa M.,Abdulrahman, Loay K.,Abu-Hammour, Khaled,AbuHammad, Shatha,Taha, Mutasem O.,Zihlif, Malek A.
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supporting information
p. 450 - 456
(2017/02/03)
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- Acetobenzylamide piperazine derivative and application thereof as cranial nerve protective agent
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The invention discloses an acetobenzylamide piperazine derivative and an application thereof as a cranial nerve protective agent. Pharmacological experiments verify that the compound disclosed by the invention shows an obvious effect against glutamic acid-induced neuron exitotoxicity in vitro and obvious anti-anoxia activity in a mouse, and a herg test further shows that the compound disclosed by the invention does not have the risk of cardiotoxicity. Therefore, the compound disclosed by the invention has the advantages of being high in activity, less in side effect and good in druggability. The compound and a medicinal preparation thereof have a good curative effect for treating cranial nerve injury diseases, for example, stroke and related diseases and do not have the risk of cardiotoxicity. The acetobenzylamide piperazine derivative is a free alkali or salt of a compound with a chemical structural formula shown in the description.
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Paragraph 0091
(2016/10/07)
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- Friedel-crafts alkylation of N-(2-chloropropionyl)aniline and the generation mechanism of byproducts
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The cyclization of N-(2-chloropropionyl)aniline to 3-methylindolin-2-one through Friedel-Crafts alkylation was studied. It was found that N-phenylacrylamide (12.6%) and 3,4-dihydro-2(1H)-quinolinone (1.5%) as main byproducts were obtained. On the basis of the mechanism of Friedel-Crafts alkylation, the generation mechanisms of these two compounds were proposed.
- Tian, Jun,Li, Lei,Yan, Xilong,Chen, Ligong
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p. 1811 - 1813
(2015/01/09)
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- GPR17-MODULATING COMPOUNDS, DIAGNOSTIC AND THERAPEUTIC USES THEREOF
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Disclosed are compounds able to modulate the activity of the GPR17 receptor in a highly specific way, which are useful in the treatment and diagnosis of diseases or dysfunctions involving the activation of said receptor. In particular, the compounds according to the invention can be used for neuroprotective and/or reparatory purposes, in cerebral, cardiac and renal ischaemia, in cerebral trauma, in chronic neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), and in demyelinating diseases such as multiple sclerosis.
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Paragraph 0046-0047
(2014/06/11)
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- Visible light photoredox-catalysed intermolecular radical addition of α-halo amides to olefins
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We present α-chloro amides as a new class of α-acetyl radical precursors, which undergo a tin-free, photoredox-catalysed intermolecular α-alkylation with various olefins exclusively in an anti-Markovnikov fashion. The reaction represents a reductive atom
- Nakajima, Masaki,Lefebvre, Quentin,Rueping, Magnus
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supporting information
p. 3619 - 3622
(2014/04/03)
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- In silico and experimental identification of non ulcerogenic antiinflammatory agents: 3-Thio substituted-4,5-diaryl-4H-1,2,4-triazoles
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A new series of 4,5 diaryl-1,2,4-triazole-3-thione substituted carboxamides have been designed, synthesized and tested for their analgesic and antiinflammatory potential. All the tested compounds exhibit antiinflammatory activity comparable to that of standard drugs rofecoxib and diclofenac. Some compounds demonstrate significant analgesic activity in contrast to reference drugs. Compound 9c has emerged as a highly potent lead compound. Ulcerogenic studies of synthesized compounds and rofecoxib show nil or negligible ulcerogenic effect compared to diclofenac. In silico analysis (docking studies) of the most active compound 9c has revealed hypothetical binding mode of the target compound to the cyclooxygenase isoenzyme (COX-2). Docking study has anticipated stereoselective binding mode for the most active compound 9c.
- Khatale, Pravin N.,Sivakumar,Mahajan, Niranjan S.,Jawarkar, Rahul D.,Kedar, Chakor K.
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p. 890 - 899
(2014/08/05)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF INFLAMMATION
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The invention relates to the compounds of formula (I) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula (I), and methods for the treatment of inflammation may he formulated for oral buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of Type II diabetes, Type I diabetes, insulin resistance, cardiovascular disease, arrhythmia, atherosclerosis, coronary artery disease, hypertriglyceridemia, dyslipidemia, retinopathy, nephropathy, neuropathy, macular adema, arthritis, osteoarthritis, rheumatoid arthritis, inflammatory bowel syndrome, neudegeneration, Alzheimer's disease, Huntington's disease. Ulcerative colitis, Crohn's disease. Multiple Sclerosis, muscular dystropthy, metabolic syndrome, fatty liver, bone diseases, inflammatory diseases.
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Paragraph 0094; 0095; 0096
(2013/12/03)
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- GPR17-MODULATING COMPOUNDS, DIAGNOSTIC AND THERAPEUTIC USES THEREOF
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Disclosed are compounds able to modulate the activity of the GPR17 receptor in a highly specific way, which are useful in the treatment and diagnosis of diseases or dysfunctions involving the activation of said receptor. In particular, the compounds accor
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Page/Page column 12-13
(2012/05/20)
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- Discovery of novel N -phenylphenoxyacetamide derivatives as EthR inhibitors and ethionamide boosters by combining high-throughput screening and synthesis
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In this paper, we describe the screening of a 14640-compound library using a novel whole mycobacteria phenotypic assay to discover inhibitors of EthR, a transcriptional repressor implicated in the innate resistance of Mycobacterium tuberculosis to the second-line antituberculosis drug ethionamide. From this screening a new chemical family of EthR inhibitors bearing an N-phenylphenoxyacetamide motif was identified. The X-ray structure of the most potent compound crystallized with EthR inspired the synthesis of a 960-member focused library. These compounds were tested in vitro using a rapid thermal shift assay on EthR to accelerate the optimization. The best compounds were synthesized on a larger scale and confirmed as potent ethionamide boosters on M. tuberculosis-infected macrophages. Finally, the cocrystallization of the best optimized analogue with EthR revealed an unexpected reorientation of the ligand in the binding pocket.
- Flipo, Marion,Willand, Nicolas,Lecat-Guillet, Nathalie,Hounsou, Candide,Desroses, Matthieu,Leroux, Florence,Lens, Zoé,Villeret, Vincent,Wohlk?nig, Alexandre,Wintjens, René,Christophe, Thierry,Kyoung Jeon, Hee,Locht, Camille,Brodin, Priscille,Baulard, Alain R,Déprez, Benoit
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supporting information; experimental part
p. 6391 - 6402
(2012/10/07)
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- Clean, reusable and low cost heterogeneous catalyst for amide synthesis
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We have developed a heterogeneous silica catalyst that can effectively catalyse amide synthesis from acid and amine, without production of toxic by-products and with the advantage of being readily available, low cost, environmentally benign and reusable. The Royal Society of Chemistry 2009.
- Comerford, James W.,Clark, James H.,MacQuarrie, Duncan J.,Breeden, Simon W.
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supporting information; experimental part
p. 2562 - 2564
(2009/10/16)
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- Mild, powerful, and robust methods for esterification, amide formation, and thioesterification between acid chlorides and alcohols, amines, thiols, respectively
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We developed two efficient practical methods for esterification, amide formation, and thioesterification between acid chlorides and alcohols, amines, thiols, respectively. The present mild and robust reaction was performed by two separate methods both by combining cheap and readily available amines, N-methylimidazole, and N,N,N′,N′-tetramethylethylenediamine (TMEDA). Method A uses catalytic N-methylimidazole and TMEDA with an equimolar amount of K2CO3, whereas Method B uses equimolar amounts of N-methylimidazole and TMEDA. The salient features are as follows. (i) With regard to reactivity, Method B was superior to Method A for esterification and thioesterification, whereas cost-effective Method A was superior to Method B for amide formation. (ii) Amide formation proceeded smoothly between acid chlorides and less nucleophilic and stereocongested amines such as 2,6-dichloroaniline. (iii) This protocol was applied to the successful synthesis of two agrochemicals, bromobutide and carpropamid.
- Nakatsuji, Hidefumi,Morimoto, Mami,Misaki, Tomonori,Tanabe, Yoo
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p. 12071 - 12080
(2008/03/13)
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- Anticancer activities of some arylcarbamoylalkyltriphenylphosphonium chlorides
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A series of novel arylcarbamoylalkyltriphenylphosphonium chlorides were synthesized. The newly synthesized compounds, [R-(p-C6H 4)-NH-CO-R1P⊕(C6H 4)3]Clθ, R = H (2), CH3 (4), NO2 (6), R1 = -CH2- (b), CH3CH2CH2- (c), -CH2CH2CH 2 (d), the analogs of an anticancer drug, were characterized by infrared (IR), 1H nuclear magnetic resonance (NMR), 13C-NMR, 31P-NMR, mass spectrometry (MS), thermogravimetry (TG), and conductivity measurements. The anticancer activities of the obtained compounds were measured by MTT. The preliminary results indicated that some compounds showed potent anticancer activities against HCT-8, Bel-7402, A549, and S180.
- Zhaowen, Lou,Li, Zhou,Chunfen, Xiao,Yong, Ye,Fanbo, Zeng,Kaixun, Huang
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p. 380 - 391
(2008/12/21)
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- Investigation of the synthetic and mechanistic aspects of the highly stereoselective transformation of α-thioamides to α-thio-β- chloroacrylamides
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Treatment of a series of α-thioamides with N-chlorosuccinimide results in efficient transformation to the analogous α-thio-β- chloroacrylamides. The mechanistic pathway has been established through isolation and characterisation of intermediate compounds. The scope of the transformation has been explored - aryl and alkylthio substituents, primary, secondary and tertiary amides can be employed. In most instances, the chloroacrylamides are formed exclusively as the Z-stereoisomer; however, with tertiary propanamides or with amides derived from butanoic or pentanoic acid a mixture of E- and Z-stereoisomers is formed. The Royal Society of Chemistry.
- Murphy, Maureen,Lynch, Denis,Schaeffer, Marcel,Kissane, Marie,Chopra, Jay,O'Brien, Elisabeth,Ford, Alan,Ferguson, George,Maguire, Anita R.
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p. 1228 - 1241
(2008/02/03)
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- A one-pot synthesis of pyrido[2,3.b][1,4]oxazin-2-ones
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Pyrido[2,3-b][1,4]oxazin-2-ones are conveniently prepared in excellent yields by a one-pot annulation of N-substituted-2-chloroacetamides with 2-halo-3-hydroxypyridines with use of cesium carbonate in refluxing acetonitrile. The key transformation features a Smiles rearrangement of the initial O-alkylation product and subsequent cyclization.
- Cho, Su-Dong,Park, Yong-Dae,Kim, Jeum-Jong,Lee, Sang-Gyeong,Ma, Chen,Song, Sang-Yong,Joo, Woo-Hong,Falck,Shiro, Motoo,Shin, Dong-Soo,Yoon, Yong-Jin
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p. 7918 - 7920
(2007/10/03)
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- AlCl3-Catalysed trans N-acylation of Acetanilides with α-Chloropropionyl Chloride
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trans N-acylation of acetanilides with α-chloropropionyl chloride catalysed by AlCl3 has been shown to occur efficiently, affording 2-chloro-N-phenylpropanamides in preparative yields.
- Sonawane,Pol,Nanjundiah,Sudalai
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- Catalytic Trans N-acylation of Anilides with α-Chloropropionyl Chloride over Zeolites
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A mild and effective method of zeolite catalyzed trans N-acylation of anilides in liquid-phase is described.
- Sonawane, H.R.,Pol, A.V.,Moghe, P.P.,Sudalai, A.,Biswas, S.S.
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p. 8877 - 8880
(2007/10/02)
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- Reaction of lithium trimethylsilyldiazomethanide with ketenimines bearing electron-withdrawing groups
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Ketenimines bearing electron-withdrawing groups (X in 1) at the C2-position react with lithium trimethylsilyldiazomethanide [diazo(lithio)trimethylsilylmethane] to give 4-amino-3-trimethylsilylpyrazoles 4 or 5 mainly; in some cases 4-trimethylsilyl-1,2,3-triazole derivatives 3 were formed as the major products.
- Aoyama,Nakano,Marumo,Uno,Shioiri
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p. 1163 - 1167
(2007/10/02)
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- 1-[N-(α-amino-α-methylacetyl)aminophenyl]-2-aminopropanone derivatives
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The present invention relates to new derivatives selected from the group consisting of: (i) 1-[N-(α-alkylamino-α-methylacetyl)aminophenyl]-2-alkylaminopropanones of the general formula: STR1 in which R represents a C1 -C4 alkyl group
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- Reaction of Silyl Enol Ethers with N-Chlorosuccinimide: Trapping the Siloxycarbinyl Cation by an Azide Anion
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Reaction of silyl enol ethers (1a-1f) with N-chlorosuccinimide afforded siloxycarbinyl cations which were trapped by nucleophiles (NaN3 and MeOH); subsequebt rearrangement of the azido products (2a,b,d,e-N3) under reflux in decalin led to anilide derivatives (3a,b,d,e).
- Ohkata, Katsuo,Mase, Mikiko,Akiba, Kin-ya
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p. 1727 - 1728
(2007/10/02)
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- Cardioselective aryloxy- and arylthio- hydroxypropylene-piperazinyl acetanilides which affect calcium entry
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Novel compounds of the general formula STR1 and the pharmaceutically acceptable esters and acid addition salts thereof, wherein: R1, R2, R3, R4 and R5 are each independently hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, N-optionally substituted alkylamido, except that when R1 is methyl, R4 is not methyl; or R2 and R3 together form --OCH2 O--; R6, R7, R8, R9 and R10 are each independently hydrogen, lower acyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, di-lower alkyl amino; or R6 and R7 together form --CH=CH--CH=CH--; R7 and R8 together form --OCH2 O--; R11 and R12 are each independently hydrogen or lower alkyl; and W is oxygen or sulfur. These cardioselective compounds have calcium entry blockade properties and therefore are useful in therapy in the treatment of cardiovascular diseases, including arrhythmias, variant and exercise induced angina and myocardial infarction.
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- BENZODIOXANYL-HYDROXYETHYLENEAMINO-PIPERIDINYL ACETANILIDES, KETONES, ESTERS AND CARBAMATES WHICH EFFECT IMMUNITY AND CALCIUM ENTRY AND BETA-BLOCKADE
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Novel compounds of the general formula: STR1 and the pharmaceutically acceptable acid addition salts thereof, wherein: R 1, R 2, R 3 and R 4 are each independently hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl or lower alkyl sulfonyl;R 5 is hydrogen or lower alkyl;m is 0 or 1;W is alkylene,--CH=CH--,--O--, or--N(R 6)--, where R 6 is lower alkyl or hydrogen;n is 0 or 1; andQ is lower alkyl, cycloalkyl or optionally substituted phenyl. These compounds combine β-blockade and calcium entry blockade properties in the same compound and therefore are useful in therapy in the treatment of cardiovascular diseases, including myocardial infarction, hypertension, arrhythmia and variant and exercise induced angina. The compounds are also useful in immunosuppressant therapy for immune diseases, such as rheumatoid arthritis.
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