- Structure-Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D2 Receptor
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Haloperidol is a typical antipsychotic drug (APD) associated with an increased risk of extrapyramidal side effects (EPSs) and hyperprolactinemia relative to atypical APDs such as clozapine. Both drugs are dopamine D2 receptor (D2R) antagonists, with contrasting kinetic profiles. Haloperidol displays fast association/slow dissociation at the D2R, whereas clozapine exhibits relatively slow association/fast dissociation. Recently, we have provided evidence that slow dissociation from the D2R predicts hyperprolactinemia, whereas fast association predicts EPS. Unfortunately, clozapine can cause severe side effects independent of its D2R action. Our results suggest an optimal kinetic profile for D2R antagonist APDs that avoids EPS. To begin exploring this hypothesis, we conducted a structure-kinetic relationship study of haloperidol and revealed that subtle structural modifications dramatically change binding kinetic rate constants, affording compounds with a clozapine-like kinetic profile. Thus, optimization of these kinetic parameters may allow development of novel APDs based on the haloperidol scaffold with improved side-effect profiles.
- Fyfe, Tim J.,Kellam, Barrie,Sykes, David A.,Capuano, Ben,Scammells, Peter J.,Lane, J. Robert,Charlton, Steven J.,Mistry, Shailesh N.
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supporting information
p. 9488 - 9520
(2019/11/11)
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- Manganese-Catalyzed Electrochemical Deconstructive Chlorination of Cycloalkanols via Alkoxy Radicals
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A manganese-catalyzed electrochemical deconstructive chlorination of cycloalkanols has been developed. This electrochemical method provides access to alkoxy radicals from alcohols and exhibits a broad substrate scope, with various cyclopropanols and cyclobutanols converted into synthetically useful β- and γ-chlorinated ketones (40 examples). Furthermore, the combination of recirculating flow electrochemistry and continuous inline purification was employed to access products on a gram scale.
- Allen, Benjamin D. W.,Hareram, Mishra Deepak,Seastram, Alex C.,McBride, Tom,Wirth, Thomas,Browne, Duncan L.,Morrill, Louis C.
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supporting information
p. 9241 - 9246
(2019/11/19)
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- Method for preparing 4-cypro methylene phenylboronic acid
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The invention discloses a method for preparing a 4-cypro methylene phenylboronic acid, and relates to the technical field of organic synthesis. The chlorobenzene is taken as the starting material, is subjected to a friedel-crafts reaction to generate 4-butanoyl chloride chlorobenzene, is subjected to a ring-closure reaction to generate 4-cypro formyl chlorobenzene, is subjected to a reduction reaction to generate 4-cypro methylene chlorobenzene, and is finally subjected to a Grignard boric acid reaction to generate the 4-cypro methylene phenylboronic acid. The cheap chlorobenzene, which is easy to get, is taken as the starting material, the preparation cost is remarkably lowered, the total molar yield of the product of 4-cypro methylene phenylboronic acid prepared through the 4-cypro methylene phenylboronic acid, the ring-closure reaction, the reduction reaction and the Grignard boric acid reaction is more than 35%, the production of the product is guaranteed on the basis of the low cost, and the method is suitable for industrial production.
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Paragraph 0021
(2017/08/31)
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- Regioselective Synthesis of Carbonyl-Containing Alkyl Chlorides via Silver-Catalyzed Ring-Opening Chlorination of Cycloalkanols
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A novel and regioselective approach to carbonyl-containing alkyl chlorides via silver-catalyzed ring-opening chlorination of cycloalkanols is reported. Concurrent C(sp3)-C(sp3) bond cleavage and C(sp3)-Cl bond formation efficiently occur with good yields under mild conditions, and the chlorinated products are readily transformed into other useful synthetic intermediates and drugs. The reaction features complete regioselectivity, high efficiency, and excellent practicality. (Chemical Equation Presented).
- Huang, Feng-Qing,Xie, Jian,Sun, Jian-Guo,Wang, Yue-Wei,Dong, Xin,Qi, Lian-Wen,Zhang, Bo
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supporting information
p. 684 - 687
(2016/03/01)
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- Synthetic method of gamma-chlorobutanone derivatives
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The invention discloses a synthetic method of gamma-chlorobutanone derivatives, and relates to a production method of inner-end and distal-end chlorinated aliphatic ketones in the technical field of chemical synthesis. Acetonitrile is taken as a solvent, manganese chloride is taken as a catalyst, tert-cyclobutanol, TMSCI (trimethylchlorosilane) and IBX (2-iodoxybenzoic acid) are subjected to a reaction, and a crude product is obtained; an organic solvent is removed through reduced-pressure concentration; the crude product is subjected to chromatography on a silica gel column with an organic solvent, and a refined product can be obtained. A synthetic route is shown in the specification, wherein R is aryl or alkyl. The raw materials used in the whole reaction process are cheap and easily available, a substrate adopted in the method has wide application range, and the whole reaction is simple and easy to operate and higher in yield; the reaction cost is reduced greatly.
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Paragraph 0039-0041
(2017/07/22)
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- The synthesis of ω-(2-aryl-1,3-dioxolan-2-yl)alkyl purine derivatives and their activity towards HIV reverse transcriptase
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Novel derivatives of 6-substituted purines were synthesized by alkylation of 6-substituted purines with various 2-(chloroalkyl)-2-aryl-1,3-dioxolanes and related compounds. Their inhibitory properties toward HIV reverse transcriptase were studied. The structure-activity relationship within the synthesized compounds was found.
- Komissarov,Valuev-Elliston,Ivanova,Kochetkov,Kritzyn
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- Acylation of Grignard reagents mediated by N-methylpyrrolidone: A remarkable selectivity for the synthesis of ketones
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An efficient user-friendly method of acylation of Grignard reagents to selectively synthesize ketones is presented, which is assisted by simple amides such as NMP, or DMF. The present chemoselective method tolerates a variety of functional groups such as ketone, ester, nitrile and other functional groups.
- Gowda, Maravanhalli Sidde,Pande, Sushanth Sudhir,Ramakrishna, Ramesha Andagar,Prabhu, Kandikere Ramaiah
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supporting information; experimental part
p. 5365 - 5368
(2011/09/13)
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- Synthesis and structure-activity relationships of 5-phenylthiophenecarboxylic acid derivatives as antirheumatic agents
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5-(Phenylthiophene)-3-carboxylic acid (2a), a metabolite of esonarimod (1), which was developed as a new antirheumatic drug, was considered as a lead compound for new antirheumatic drugs. A new series of 2a derivatives were synthesized and their characteristic pharmacological effects, that is their antagonistic effect toward interleukin (IL)-1 in mice and the suppressive effect against adjuvant-induced arthritis (AIA) in rats, were evaluated and compared with those of 1. The structure-activity relationships indicated that [5-(4-bromophenyl)-thiophen-3-yl]acetic acid (5d), methyl [5-(4-chlorophenyl)-thiophen-3-yl]acetate (5h), and methyl [5-(4-bromophenyl)-thiophen-3-yl]acetate (5i) suppressed AIA more potently than 1 and all of the other synthesized compounds.
- Noguchi, Toshiya,Hasegawa, Masahiro,Tomisawa, Kazuyuki,Mitsukuchi, Morihiro
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p. 4729 - 4742
(2007/10/03)
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- Preparation and reactivity of functionalized aryl and alkenylmanganese halides
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Various functionalized aryl and alkenyl manganese halides have been prepared from the corresponding aryl and alkenylhalides according to a one-pot procedure: lithium-halogen exchange at low temperature then Li-Mn transmetallation.
- Klement, Ingo,Stadtmueller, Heinz,Knochel, Paul,Cahiez, Gerard
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p. 1927 - 1930
(2007/10/03)
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- 1-[1-aryl-1-hydroxy-2-azolyl-ethyl]-1-aryl-cyclopropane derivatives, and their fungicidal use thereof
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Compounds I STR1 where A equals t-butyl or a large number of (substituted) aromatics; Y equals azolyl; or Y equals --X--R1 where X=oxygen or sulfur and R1 equals (cyclo)alkyl or (heterocyclic) aryl; or Y equals STR2 where R2 equals (cyclo)alkyl, acetyl or aryl; or Y equals --NR3 R4 where R3 /R4 is alkyl; or Y equals several nitrogen-containing heterocyclic rings; Z equals OH, alkylcarbonyloxy, hal, alkoxy or benzyloxy; and the salts thereof are effective antimycotics or fungicides. They are obtained by reaction of II STR3 with (CH3)2 STR4 and further reaction of the compound IV STR5 obtained from this with a nucleophile YM (M=hydrogen or a metal equivalent). The compounds I (where Z=OH) resulting from this can be acylated or alkylated, or converted into I where Z=hal.
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- 4-Arylcyclohexylamines
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The invention relates to novel 4-hydroxymethyl(acyloxymethyl and methyl)-4-arylcyclohexylamines embraced by the formula SPC1 Wherein Ar is an aromatic ring selected from the group consisting of phenyl and naphthyl, each of which has from zero through three substituents independently selected from the group consisting of fluorine, chlorine, bromine, lower alkyl of one through three carbon atoms, lower alkoxy of one through three carbon atoms, and lower alkylthio of one through three carbon atoms; Z is selected from the group consisting of hydrogen, hydroxy and lower acyloxy of one through four carbon atoms; ? is a generic expression denoting cis and trans stereoconfiguration and mixtures thereof, with the proviso that when the stereoconfiguration of the linkage connecting the cyclohexane ring and CH2 Z is cis to the amino group, the linkage connecting the cyclohexane and Ar rings is trans, and vice versa; R1 is selected from the group consisting of hydrogen and lower alkyl of one through three carbon atoms; R2 is selected from the group consisting of hydrogen, lower alkyl of one through three carbon atoms, EQU1 WHEREIN N IS 2 THROUGH 5 AND Ar has the same meaning as above; R1 and R2 taken together with --N is a saturated heterocyclic amino radical selected from the group consisting of unsubstituted and substituted pyrrolidino, piperidino, hexamethylenimino, morpholino and piperazino; and pharmacologically acceptable acid addition salts thereof. It also relates to intermediates and processes for the preparation of the aforesaid novel compounds (I) and novel derivatives thereof. The administration to humans and animals of the novel compounds (I) depresses their central nervous systems and lowers their blood pressures.
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