- B(C6F5)3-Catalyzed Diastereoselective Formal (4 + 1)-Cycloaddition of Vinylcyclopropanes and Et2SiH2
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A formal (4 + 1)-cycloaddition of vinylcyclopropanes and Et2SiH2 to afford 3,4-disubstituted silolanes is reported. The reaction sequence commences with the known B(C6F5)3-catalyzed alkene hydrosilylation with dihydrosilanes. Cleavage of the remaining Si-H bond in the hydrosilylation product assisted by B(C6F5)3 leads to formation of a cyclopropane-stabilized silylium ion. The activated cyclopropane ring is then opened by the in situ-generated borohydride accompanied by ring closure to the silolane. The diastereoselectivity is rationalized by a mechanistic model.
- Long, Peng-Wei,Oestreich, Martin
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supporting information
p. 4834 - 4837
(2021/06/28)
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- Chemical modification-mediated optimisation of bronchodilatory activity of mepenzolate, a muscarinic receptor antagonist with anti-inflammatory activity
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The treatment for patients with chronic obstructive pulmonary disease (COPD) usually involves a combination of anti-inflammatory and bronchodilatory drugs. We recently found that mepenzolate bromide (1) and its derivative, 3-(2-hydroxy-2, 2-diphenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (5), have both anti-inflammatory and bronchodilatory activities. We chemically modified 5 with a view to obtain derivatives with both anti-inflammatory and longer-lasting bronchodilatory activities. Among the synthesized compounds, (R)-(–)-12 ((R)-3-(2-hydroxy-2,2-diphenylacetoxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane bromide) showed the highest affinity in vitro for the human muscarinic M3 receptor (hM3R). Compared to 1 and 5, (R)-(–)-12 exhibited longer-lasting bronchodilatory activity and equivalent anti-inflammatory effect in mice. The long-term intratracheal administration of (R)-(–)-12 suppressed porcine pancreatic elastase-induced pulmonary emphysema in mice, whereas the same procedure with a long-acting muscarinic antagonist used clinically (tiotropium bromide) did not. These results suggest that (R)-(–)-12 might be therapeutically beneficial for use with COPD patients given the improved effects seen against both inflammatory pulmonary emphysema and airflow limitation in this animal model.
- Yamashita, Yasunobu,Tanaka, Ken-ichiro,Yamakawa,Asano,Kanda, Yuki,Takafuji,Kawahara, Masahiro,Takenaga, Mitsuko,Fukunishi, Yoshifumi,Mizushima
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p. 3339 - 3346
(2019/06/18)
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- Anodic benzylic C(sp3)-H amination: Unified access to pyrrolidines and piperidines
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An electrochemical aliphatic C-H amination strategy was developed to access the important heterocyclic motifs of pyrrolidines and piperidines within a uniform reaction protocol. The mechanism of this unprecedented C-H amination strategy involves anodic C-H activation to generate a benzylic cation, which is efficiently trapped by a nitrogen nucleophile. The applicability of the process is demonstrated for 40 examples comprising both 5- and 6-membered ring formations.
- Herold, Sebastian,Bafaluy, Daniel,Mu?iz, Kilian
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supporting information
p. 3191 - 3196
(2018/07/29)
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- Derisking the Cu-Mediated 18F-Fluorination of Heterocyclic Positron Emission Tomography Radioligands
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Molecules labeled with fluorine-18 (18F) are used in positron emission tomography to visualize, characterize and measure biological processes in the body. Despite recent advances in the incorporation of 18F onto arenes, the development of general and efficient approaches to label radioligands necessary for drug discovery programs remains a significant task. This full account describes a derisking approach toward the radiosynthesis of heterocyclic positron emission tomography (PET) radioligands using the copper-mediated 18F-fluorination of aryl boron reagents with 18F-fluoride as a model reaction. This approach is based on a study examining how the presence of heterocycles commonly used in drug development affects the efficiency of 18F-fluorination for a representative aryl boron reagent, and on the labeling of more than 50 (hetero)aryl boronic esters. This set of data allows for the application of this derisking strategy to the successful radiosynthesis of seven structurally complex pharmaceutically relevant heterocycle-containing molecules.
- Taylor, Nicholas J.,Emer, Enrico,Preshlock, Sean,Schedler, Michael,Tredwell, Matthew,Verhoog, Stefan,Mercier, Joel,Genicot, Christophe,Gouverneur, Véronique
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supporting information
p. 8267 - 8276
(2017/06/27)
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- DIRECT PALLADIUM-CATALYZED AROMATIC FLUORINATION
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Provided herein are palladium complexes comprising a ligand of Formula (Α') and a ligand of Formula (B), wherein R1-R18 are as defined herein. The palladium complexes are useful in methods of fluorinating aryl and heteroaryl substrates. Further provided are compositions and kits comprising the palladium complexes.
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Paragraph 00201; 00202
(2017/09/27)
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- NOVEL COMPOUND, ORGANIC CATION TRANSPORTER 3 DETECTION AGENT, AND ORGANIC CATION TRANSPORTER 3 ACTIVITY INHIBITOR
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[Problem] The present invention addresses the problem of providing a novel compound. The present invention also addresses the problem of providing an OCT3 detection agent or an OCT3 activity inhibitor, which comprises the novel compound. [Solution] A compound represented by formula (A), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. ????????R1-R2-R3-R4?????(A)
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Paragraph 0661-0664
(2016/08/17)
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- 4-alkyloxyimino derivatives of uridine-5′-triphosphate: Distal modification of potent agonists as a strategy for molecular probes of P2Y 2, P2Y4, and P2Y6 receptors
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Extended N4-(3-arylpropyl)oxy derivatives of uridine-5′-triphosphate were synthesized and potently stimulated phospholipase C stimulation in astrocytoma cells expressing G protein-coupled human (h) P2Y receptors (P2YRs) activated by UTP (P2Y2/4R) or UDP (P2Y6R). The potent P2Y4R-selective N4-(3- phenylpropyl)oxy agonist was phenyl ring-substituted or replaced with terminal heterocyclic or naphthyl rings with retention of P2YR potency. This broad tolerance for steric bulk in a distal region was not observed for dinucleoside tetraphosphate agonists with both nucleobases substituted. The potent N 4-(3-(4-methoxyphenyl)-propyl)oxy analogue 19 (EC50: P2Y2R, 47 nM; P2Y4R, 23 nM) was functionalized for chain extension using click tethering of fluorophores as prosthetic groups. The BODIPY 630/650 conjugate 28 (MRS4162) exhibited EC50 values of 70, 66, and 23 nM at the hP2Y2/4/6Rs, respectively, and specifically labeled cells expressing the P2Y6R. Thus, an extended N4-(3- arylpropyl)oxy group accessed a structurally permissive region on three G q-coupled P2YRs, and potency and selectivity were modulated by distal structural changes. This freedom of substitution was utilized to design of a pan-agonist fluorescent probe of a subset of uracil nucleotide-activated hP2YRs.
- Jayasekara, P. Suresh,Barrett, Matthew O.,Ball, Christopher B.,Brown, Kyle A.,Hammes, Eva,Balasubramanian, Ramachandran,Harden, T. Kendall,Jacobson, Kenneth A.
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p. 3874 - 3883
(2014/05/20)
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- HETEROCYCLIC COMPOUNDS AND METHODS FOR THEIR USE
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The present invention relates to heterocyclic compounds useful for antagonising angiotensin II Type 2 (AT2) receptor. More particularly the invention relates to pyrrolidine and azetidine compounds, compositions containing them and their use in methods of treating or preventing disorders or diseases associated with AT2 receptor function including neuropathic pain, inflammatory pain, conditions associated with neuronal hypersensitivity, impaired nerve conduction velocity, cell proliferation disorders, disorders associated with an imbalance between bone resorption and bone formation and disorders associated with aberrant nerve regeneration.
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- 3-Hydroxypyrimidine-2,4-diones as an Inhibitor Scaffold of HIV Integrase
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Integrase (IN) represents a clinically validated target for the development of antivirals against human immunodeficiency virus (HIV). Inhibitors with a novel structure core are essential for combating resistance associated with known IN inhibitors (INIs). We have previously disclosed a novel dual inhibitor scaffold of HIV IN and reverse transcriptase (RT). Here we report the complete structure-activity relationship (SAR), molecular modeling, and resistance profile of this inhibitor type on IN inhibition. These studies support an antiviral mechanism of dual inhibition against both IN and RT and validate 3-hydroxypyrimidine-2,4-diones as an IN inhibitor scaffold.
- Tang, Jing,Maddali, Kasthuraiah,Metifiot, Mathieu,Sham, Yuk Y.,Vince, Robert,Pommier, Yves,Wang, Zhengqiang
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experimental part
p. 2282 - 2292
(2011/06/17)
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- AMINE COMPOUND AND PHARMACEUTICAL USE THEREOF
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Provided is a novel amine compound represented by the following formula (I) having a superior peripheral blood lymphocyte decreasing action and superior in the immunosuppressive action, rejection suppressive action and the like, which shows decreased side effects of, for example, bradycardia and the like, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, or a solvate thereof. wherein each symbol is as defined in the specification.
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Page/Page column 62
(2010/04/25)
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- Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17α-hydroxylase/17,20-lyase (P45017α)
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We report the preliminary results of the synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a number of phenyl alkyl imidazole-based compounds as inhibitors of the two components of 17α-hydroxylase/17,20-lyase (P45017α), that is, 17α-hydroxylase (17α-OHase) and 17,20-lyase (lyase). The results show that N-3-(4-bromophenyl) propyl imidazole (12) (IC50 = 2.95 μM against 17α-OHase and IC50 = 0.33 μM against lyase) is the most potent compound within the current study, in comparison to ketoconazole (KTZ) (IC50 = 3.76 μM against 17α-OHase and IC50 = 1.66 μM against lyase). Modelling of these compounds suggests that the length of the alkyl chain enhances the interaction between the inhibitor and the area of the active site corresponding to the C(3) area of the steroid backbone, thereby increasing potency.
- Patel, Chirag H.,Dhanani, Sachin,Owen, Caroline P.,Ahmed, Sabbir
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p. 4752 - 4756
(2007/10/03)
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- N-UREIDOALKYL-AMINO COMPOUNDS AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
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The present application describes modulators of chemokine receptors of formula (I), or pharmaceutically acceptable salt forms thereof, useful for the prevention of asthma and other allergic diseases.
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- Indoles
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A 1,4-substituted cyclic amine derivative represented by the following formula or a pharmacologically acceptable salt thereof: wherein A, B, C, D, T, Y, and Z each represent a methine or a nitrogen linkage; R1, R2, R3, R4, and R5 each represent a substituent; n represents 0 or an integer of 1 to 3; m represents 0 or an integer of 1 to 6; and p represents an integer of 1 to 3. The compounds have serotonin antagonism. They are therefore clinically useful as medicaments, in particular, for treating, ameliorating, and preventing spastic paralysis. They are also useful as central muscle relaxants for ameliorating myotonia.
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- Pharmacophore-based discovery, synthesis, and biological evaluation of 4-phenyl-1-arylalkyl piperidines as dopamine transporter inhibitors
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Pharmacophore-based discovery, synthesis, and structure-activity relationship (SAR) of a series of 4-phenyl-1-arylalkyl piperidines are disclosed. These compounds have been evaluated for their ability to inhibit reuptake of dopamine (DA) into striatal nerve endings (synaptosomes). The lead compound 5 and the most potent analogue 43 were found to have significant functional antagonism.
- Sakamuri, Sukumar,Enyedy, Istvan J,Kozikowski, Alan P,Zaman, Wahiduz A,Johnson, Kenneth M,Wang, Shaomeng
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p. 495 - 500
(2007/10/03)
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- Antiviral composition
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N-Substituted-1-deoxynojirimycin derivatives such as N-(3-phenylpropyl)-1-deoxynojirimycin can effectively inhibit the formation of giant cells and are useful for therapy and prophylaxis of AIDS.
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- The Copper Halide-Catalyzed Mono-Substitution of Bromine in α,ω-Dibromoalkanes by Grignard Reagents. A Reinvestigation
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α,ω-Dibromoalkanes have been converted into mono-bromides R(CH2)nBr by reaction with the Grignard compounds RMgBr in THF in the presence of 5 mol percent of copper(I)bromide.In contrast to what is suggested in the original literature, this method has a limited scope.
- Andringa, H.,Hanekamp, J.,Brandsma, L.
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p. 2349 - 2351
(2007/10/02)
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- Drugs derived from cannabinoids. 5. Δ(6a,10a) Tetrahydrocannabinol and heterocyclic analogs containing aromatic side chains
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Ten new Δ(6a,10a) THC analogs with arylalkyl side chains, one with a dimethylaminoalkyl side chain, and six heterocyclic Δ(6a,10a) THC analogs [8 substituted 5,5 dimethyl 10 hydroxy 2 (2 propynyl) 1,2,3,4 tetrahydro 5H [1] benzo pyranol [4,3 c] pyridines] were prepared. They showed pharmacological activity as analgesics, tranquilizers, antihypertensives, and hypnotics and as antisecretory, antiulcer, and antidiarrheal agents. The most potent compounds had either a 1 methyl 4 (4 fluorophenyl) butyl or a 1,2 dimethyl 4 (4 fluorophenyl) butyl side chain.
- Winn,Arendsen,Dodge,Dren,Dunnigan,Hallas,Hwang,Kyncl,Lee,Plotnikoff,Young,Zaugg
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p. 461 - 471
(2007/10/05)
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