- Catalytic N-Acylation of Cyclic Amines by Arylglyoxylic Acids via Radical-Radical Cross-Coupling
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A methodical mechanistic investigation allowed for the catalytic N-acylation of secondary cyclic amine counterparts by arylglyoxylic acids through radical-radical coupling. The reaction proceeds via a twofold SET-promoted Cu(I)/Cu(II) catalytic cycle under mild conditions. An analogous reaction variant allows for the N-acylation in a one-pot fashion directly starting from a secondary cyclic amine even in the presence of a second amine or hydroxy group.
- Bhadra, Sukalyan,Gupta, Aniket,Kumar Singh, Anupam,Rahaman, Ajijur
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supporting information
p. 2198 - 2202
(2021/07/22)
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- COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF PARASITIC DISEASES
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The present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt thereof; a method for manufacturing the compounds of the invention, solid forms, combinations of pharmacologically active agents, pharmaceutical compositions and methods of using such compounds and solid forms thereof to treat or prevent parasitic diseases, for example malaria.
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Paragraph 0681; 0695-0697
(2021/04/23)
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- Optimization of a Benzoylpiperidine Class Identifies a Highly Potent and Selective Reversible Monoacylglycerol Lipase (MAGL) Inhibitor
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Monoacylglycerol lipase (MAGL) is the enzyme degrading the endocannabinoid 2-arachidonoylglycerol, and it is involved in several physiological and pathological processes. The therapeutic potential of MAGL is linked to several diseases, including cancer. The development of MAGL inhibitors has been greatly limited by the side effects associated with the prolonged MAGL inactivation. Importantly, it could be preferable to use reversible MAGL inhibitors in vivo, but nowadays only few reversible compounds have been developed. In the present study, structural optimization of a previously developed class of MAGL inhibitors led to the identification of compound 23, which proved to be a very potent reversible MAGL inhibitor (IC50 = 80 nM), selective for MAGL over the other main components of the endocannabinoid system, endowed of a promising antiproliferative activity in a series of cancer cell lines and able to block MAGL both in cell-based as well as in vivo assays.
- Granchi, Carlotta,Lapillo, Margherita,Glasmacher, Sandra,Bononi, Giulia,Licari, Cristina,Poli, Giulio,El Boustani, Maguie,Caligiuri, Isabella,Rizzolio, Flavio,Gertsch, Jürg,Macchia, Marco,Minutolo, Filippo,Tuccinardi, Tiziano,Chicca, Andrea
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p. 1932 - 1958
(2019/02/26)
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- Methyl Esters as Cross-Coupling Electrophiles: Direct Synthesis of Amide Bonds
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Amide bond formation and transition metal-catalyzed cross-coupling are two of the most frequently used chemical reactions in organic synthesis. Recently, an overlap between these two reaction families was identified when Pd and Ni catalysts were demonstrated to cleave the strong C-O bond present in esters via oxidative addition. When simple methyl and ethyl esters are used, this transformation provides a powerful alternative to classical amide bond formations, which commonly feature stoichiometric activating agents. Thus far, few redox-active catalysts have been demonstrated to activate the C(acyl)-O bond of alkyl esters, which makes it difficult to perform informed screening when a challenging reaction needs optimization. We demonstrate that Ni catalysts bearing diverse NHC, phosphine, and nitrogen-containing ligands can all be used to activate methyl esters and enable their use in direct amide bond formation.
- Zheng, Yan-Long,Newman, Stephen G.
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p. 4426 - 4433
(2019/05/08)
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- CASPASE INHIBITOR AND PHARMACEUTICAL COMPOSITION, USE AND THERAPEUTIC METHOD THEREOF
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Disclosed are a class of compounds as a caspase inhibitor, and in particular the compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, and the use of the compound in treating caspase-related diseases.
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Paragraph 0256; 0257
(2019/04/05)
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- An Epoxide-Mediated Deprotection Method for Acidic Amide Auxiliary
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A practical method for the removal of a versatile acidic amide auxiliary has been developed. Facile alcoholysis of the amide in the presence of KOAc is enabled by an epoxide, which mechanistically resembles the removal of the Myers' auxiliary. The protocol has been applied to the removal of a variety of amide substrates and their C-H functionalization products with high efficiency and low cost, representing a step forward toward the development of a versatile directing group for C-H activation.
- Pei, Qing-Lan,Che, Guan-Da,Zhu, Ru-Yi,He, Jian,Yu, Jin-Quan
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supporting information
p. 5860 - 5863
(2017/11/10)
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- Rational Design, Pharmacomodulation, and Synthesis of Dual 5-Hydroxytryptamine 7 (5-HT7)/5-Hydroxytryptamine 2A (5-HT2A) Receptor Antagonists and Evaluation by [18F]-PET Imaging in a Primate Brain
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We report the synthesis of 46 tertiary amine-bearing N-alkylated benzo[d]imidazol-2(3H)-ones, imidazo[4,5-b]pyridin-2(3H)-ones, imidazo[4,5-c]pyridin-2(3H)-ones, benzo[d]oxazol-2(3H)-ones, oxazolo[4,5-b]pyridin-2(3H)-ones and N,N′-dialkylated benzo[d]imidazol-2(3H)-ones. These compounds were evaluated against 5-HT7R, 5-HT2AR, 5-HT1AR, and 5-HT6R as potent dual 5-HT7/5-HT2A serotonin receptors ligands. A thorough study of the structure-activity relationship of the aromatic rings and their substituents, the alkyl chain length and the tertiary amine was conducted. 1-(4-(4-(4-Fluorobenzoyl)piperidin-1-yl)butyl)-1H-benzo[d]imidazol-2(3H)-one (79) and 1-(6-(4-(4-fluorobenzoyl)piperidin-1-yl)hexyl)-1H-benzo[d]imidazol-2(3H)-one (81) were identified as full antagonist ligands on cyclic adenosine monophosphate (cAMP, KB = 4.9 and 5.9 nM, respectively) and inositol monophosphate (IP1, KB = 0.6 and 16 nM, respectively) signaling pathways of 5-HT7R and 5-HT2AR. Both antagonists crossed the blood-brain barrier as evaluated with [18F] radiolabeled compounds [18F]79 and [18F]81 in a primate's central nervous system using positron emission tomography. Both radioligands showed standard uptake values ranging from 0.8 to 1.1, a good plasmatic stability, and a distribution consistent with 5-HT7R and 5-HT2AR in the CNS.
- Deau, Emmanuel,Robin, Elodie,Voinea, Raluca,Percina, Nathalie,Sata?a, Grzegorz,Finaru, Adriana-Luminita,Chartier, Agnès,Tamagnan, Gilles,Alagille, David,Bojarski, Andrzej J.,Morisset-Lopez, Séverine,Suzenet, Franck,Guillaumet, Gérald
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p. 8066 - 8096
(2015/11/09)
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- Alkoxycarbonylpiperidines as N-nucleophiles in the palladium-catalyzed aminocarbonylation
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Piperidines possessing ester functionality, such as 2-(methoxycarbonyl) piperidine (methyl pipecolinate), 3-(ethoxycarbonyl)piperidine (ethyl nipecotate), and 4-(ethoxycarbonyl)piperidine (ethyl isonipecotate), were used as N-nucleophiles in palladium-cat
- Takacs, Attila,Kabak-Solt, Zsuzsanna,Mikle, Gabor,Kollar, Laszlo
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p. 1473 - 1478
(2014/10/15)
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- PYRROLO[2,3-D]PYRIMIDINE DERIVATIVE
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Provided is a compound represented by the Formula (I) having a HER2 inhibitory action or a pharmacologically acceptable salt thereof, wherein T1 is a phenyl group, an indazolyl group, or a benzofuryl group, n is an integer of 0 to 3, R1 /
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Page/Page column 22
(2012/06/18)
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- Synthesis and in vitro biological evaluation of carbonyl group-containing inhibitors of vesicular acetylcholine transporter
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To identify selective high-affinity inhibitors of the vesicular acetylcholine transporter (VAChT), we have interposed a carbonyl group between the phenyl and piperidyl groups of the prototypical VAChT ligand vesamicol and its more potent analogues benzovesamicol and 5-aminobenzovesamicol. Of 33 compounds synthesized and tested, 6 display very high affinity for VAChT (K i, 0.25-0.66 nM) and greater than 500-fold selectivity for VAChT over σ1 and σ2 receptors. Twelve compounds have high affinity (Ki, 1.0-10 nM) and good selectivity for VAChT. Furthermore, 3 halogenated compounds, namely, trans-3-[4-(4-fluorobenzoyl) piperidinyl]-2-hydroxy-1,2,3,4-tetrahydronaphthalene (28b) (Ki = 2.7 nM, VAChT/sigma selectivity index = 70), trans-3-[4-(5-iodothienylcarbonyl) piperidinyl]-2-hydroxy-1,2,3,4-tetrahydronaphthalene (28h) (Ki = 0.66 nM, VAChT/sigma selectivity index = 294), and 5-amino-3-[4-(p-fluorobenzoyl) piperidinyl]-2-hydroxy-1,2,3,4,-tetrahydronaphthalene (30b) (Ki = 2.40 nM, VAChT/sigma selectivity index = 410) display moderate to high selectivity for VAChT. These three compounds can be synthesized with the corresponding radioisotopes so as to serve as PET/SPECT probes for imaging the VAChT in vivo.
- Efange, Simon M. N.,Khare, Anil B.,Von Hohenberg, Krystyna,MacH, Robert H.,Parsons, Stanley M.,Tu, Zhude
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scheme or table
p. 2825 - 2835
(2010/08/05)
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- Synthesis and in vitro and in vivo evaluation of18F-labeled positron emission tomography (PET) ligands for imaging the vesicular acetylcholine transporter
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A new class of vesicular acetylcholine transporter inhibitor that incorporates a carbonyl group into the benzovesamicol structure was synthesized, and analogues were evaluated in vitro. (±)-trans-2-Hydroxy-3- (4-(4-[18F]fluorobenzoyl)piperidino)tetralin (9e) has Ki values of 2.70 nM for VAChT, 191 nM for σ1 and 251 nM for σ2. The racemic precursor (9d) was resolved via chiral HPLC, and (±)-[18F]9e,(-)-[18F]9e, and (+)-[ 18F]9e were respectively radiolabeled via microwave irradiation of the appropriate precursors with [18F]/F- and Kryptofix/K 2CO3 in DMSO with radiochemical yields of ~50-60% and specific activities of >2000 mCi/μmol. (-)-[18F]9e uptake in rat brain was consistent with in vivo selectivity for the VAChT with an initial uptake of 0.911 %ID/g in rat striatum and a striatum/cerebellum ratio of 1.88 at 30 min postinjection (p.i.). MicroPET imaging of macaques demonstrated a 2.1 ratio of (-)-[18F]9e in putamen versus cerebellum at 2 h p.i. (-)-[18F]9e has potential to be a PET tracer for clinical imaging of the VAChT.
- Tu, Zhude,Efange, Simon M. N.,Xu, Jinbin,Li, Shihong,Jones, Lynne A.,Parsons, Stanley M.,Mach, Robert H.
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experimental part
p. 1358 - 1369
(2009/12/26)
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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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- Synthesis of diarylazepan-4-ones
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Synthesis of several 3,3-diarylazepan-4-ones and 5,5-diarylazepan-4-ones has been established starting from two tetrasubstituted olefins, which is derived from commercially available piperidine-3-carboxylic acid ethyl ester and piperidine-4-carboxylic aci
- Chang, Meng-Yang,Kung, Yung-Hua,Ma, Chih-Chong
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p. 199 - 202
(2007/10/03)
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- Synthesis and evaluation of tacrine-E2020 hybrids as acetylcholinesterase inhibitors for the treatment of Alzheimer's disease
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Tacrine-E2020 hybrids and some related compounds were prepared and their bioactivities on the Alzheimer's Disease were assayed. The optimum hybrid inhibitor 3 is much more potent and selective than tacrine in vitro. Tacrine-E2020 hybrids and some related compounds were prepared and their bioactivities on the Alzheimer's disease were assayed. The optimum hybrid inhibitor 3 is 37-fold more potent and 31-fold more selective than tacrine in vitro.
- Shao, Dong,Zou, Chunyan,Luo, Cheng,Tang, Xican,Li, Yuanchao
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p. 4639 - 4642
(2007/10/03)
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- Alpha IC adrenergic receptor antagonists
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This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as selective alpha-1C adrenergic receptor antagonists. One application of these compounds is in the treatment of benign prostatic hypertrophy. These compounds are selective in their ability to relax smooth muscle tissue enriched in the alpha1C receptor subtype without at the same time inducing orthostatic hypotension. One such tissue is found surrounding the urethral lining. Therefore, one utility of the instant compounds is to provide acute relief to males suffering from benign prostatic hyperplasia, by permitting less hindered urine flow. Another utility of the instant compounds is provided by combination with a human 5-alpha reductase inhibitory compound, such that both acute and chronic relief from the effects of benign prostatic hyperplasia are achieved.
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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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- Reductive alkylation of pyridinium salts. Part 2. Utilisation of di-, tetra- and hexa-hydropyridine esters
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4-Benzyl-4-ethoxycarbonyl-1-substituted piperidines 1 (R1 = PhCH2, PhCO; R2 = PhCH2) cyclise with polyphosphoric acid (PPA) to give spiro[indane-2,4′-piperidin]-1-ones 3 (R = PhCH2, PhCO), while 2-benzyl-2-ethoxycarbonyl-1-methylpiperidine 4 gives the N-methylspiro[indane-2,2′-piperidin]-1-one 5. 3,4,4a,5-Tetrahydrobenz[g]isoquinolin-10(2H)-one 8 arises from PPA treatment of 1-benzoyl-4-benzyl-5-ethoxycarbonyl-1,2,3,4-tetrahydropyridine 7 (R = PhCO) while o-chloranil converts 1-benzoyl-4-benzyl-4-ethoxycarbonyl-1,4-dihydropyridine 6 (R = PhCO) into 4-benzyl-3-ethoxycarbonylpyridine 9. Phenyl(tribromomethyl)mercury reacts with 1-benzoyl-4-benzyl-4-ethoxycarbonyl-1,4-dihydropyridine 2 (R1 = PhCO, R2 = PhCH2) yielding 2-benzoyl-5-benzyl-7,7-dibromo-5-ethoxycarbonyl-2-azabicyclo[4.1.0]hept-3-ene 11, and with 1-benzoyl-4-benzyl-3-ethoxycarbonyl-1,4-dihydropyridine 6 (R = PhCO) to give 2-benzoyl-5-benzyl-7,7-dibromo-4-ethoxycarbonyl-2-azabicyclo[4.1.0]hept-3-ene 12. The structure of the latter is confirmed by X-ray crystallographic analysis. Catalytic hydrogenation of 2-benzoyl-5-benzyl-7,7-dichloro-5-ethoxycarbonyl-2-azabicyclo[4.1.0]hept-3-ene 16 yields 2-benzoyl-5-benzyl-7,7-dichloro-5-ethoxycarbonyl-2-azabicyclo[4.1.0]heptane 21 which cyclises with PPA to give the tetracyclic product 22 in good yield. When 2-benzoyl-5-benzyl-7,7-dichloro-4-ethoxycarbonyl-2-azabicyclo[4.1.0]hept-3-ene 17 is hydrogenated it yields mainly 2-benzoyl-5-benzyl-7,7-dichloro-4-ethoxycarbonyl-2-azabicyclo[4.1.0]heptane 25 but the dibromo analogue 12 under the same conditions gives two components thought to be 2-benzoyl-5-benzyl-7-endo-bromo-4-ethoxycarbonyl-2-azabicyclo[4.1.0]hept-3-ene 24 and 2-benzoyl-5-benzyl-7-exo-bromo-4-ethoxycarbonyl-2-azabicyclo[4.1.0]hept-3-ene 23. Copyright 1996 by the Royal Society of Chemistry.
- McCullough, Kevin J.,MacTavish, John,Proctor, George R.,Redpath, James
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p. 2553 - 2559
(2007/10/03)
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- N-(isoquinolin-5-ylsulphonyl) azacycloalkanes
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Compounds of formula (I): STR1 wherein R1, R2, U, X, Y, Z, n, m, p and r are as defined in the description, and medicaments containing the same.
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