- NITROGENOUS HETEROCYCLIC AMIDE DERIVATIVE, PREPARATION METHOD THEREOF, AND PHARMACEUTICAL APPLICATION
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Provided are a compound represented by formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic mixture, or prodrug thereof, and a preparation method thereof, and an application for preparing a pharmaceutical product for treating a disease related to obstructed airways, wherein each substituent in the compound represented by formula (I) is as described in the specification.
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Paragraph 0116
(2018/12/07)
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- Transition-metal-free synthesis of 3-(1-pyrrolidinyl)quinolines and 3-(1-pyrrolidinyl)quinoline 1-oxides via a one-pot reaction of 3-(1-pyrrolidinyl)crotonates with nitrobenzenes
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A carbanion of tert-butyl 3-(1-pyrrolidinyl)crotonate adds to nitrobenzenes to form σH-adducts, which in the presence of pivaloyl chloride and triethylamine are converted into 3-(1-pyrrolidinyl)quinolines or 3-(1-pyrrolidinyl)quinoline 1-oxides depending on the nitrobenzene structure. This is the first methodology in which a quinoline ring is constructed from a substrate bearing a pyrrolidinyl ring. Starting from optically pure enamines, the method allows synthesis of the corresponding chiral products without racemisation.
- Bujok, Robert,Cmoch, Piotr,Wróbel, Zbigniew,Wojciechowski, Krzysztof
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p. 2397 - 2402
(2017/03/20)
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- Synthesis and determination of absolute configuration of a non-peptidic αvβ6 integrin antagonist for the treatment of idiopathic pulmonary fibrosis
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A diastereoselective synthesis of (S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid (1), a potential therapeutic agent for the treatment of Idiopathic Pulmonary Fibrosis, which is currently undergoing Phase I clinical trials is reported. The key steps in the synthesis involved alkylation of 2-methylnaphthyridine with (R)-N-Boc-3-(iodomethyl)-pyrrolidine, and an asymmetric Rh-catalysed addition of an arylboronic acid to a 4-(N-pyrrolidinyl)crotonate ester. The overall yield of the seven linear step synthesis was 8% and the product was obtained in >99.5% ee proceeding with 80% de. The absolute configuration of 1 was established by an alternative asymmetric synthesis involving alkylation of an arylacetic acid using Evans oxazolidinone chemistry, acylation using the resulting 2-arylsuccinic acid, and reduction. The absolute configuration of the benzylic asymmetric centre was established as (S).
- Anderson, Niall A.,Campbell, Ian B.,Fallon, Brendan J.,Lynn, Sean M.,Macdonald, Simon J. F.,Pritchard, John M.,Procopiou, Panayiotis A.,Sollis, Steven L.,Thorp, Lee R.
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p. 5992 - 6009
(2016/07/06)
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- INDAZOLE- AND PYRROLOPYRIDINE-DERIVATIVE AND PHARMACEUTICAL USE THEREOF
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The present invention relates to a novel indazole- or pyrrolopyridine-derivative, represented by the formula (1) below, that has an agonistic action or a partial agonistic action against serotonin-4 receptor, and a pharmaceutical composition comprising the same. Formula (1) [wherein each substituent is as defined in claim 1]
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Page/Page column 164; 165
(2013/02/27)
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- PYRIMIDONE DERIVATIVES USED AS TAU PROTEIN KINASE 1 INHIBITORS
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A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof: wherein Z represents nitrogen atom or C-X; X represents hydrogen atom or fluorine atom; R1 is hydrogen atom or a C1 -C3 alkyl group; L represents single bond or a C1 -C6 alkylene group which may be substituted; Y represents single bond, sulfur atom, oxygen atom, NH, or the like; R2 represents hydrogen atom or a cyclic group which may be substituted, which is used for preventive and/or therapeutic treatment of a disease caused by abnormal activity of tau protein kinase 1 such as a neurodegenerative diseases (e.g. Alzheimer disease).
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- N-(HETERO)ARYL-PYRROLIDINE DERIVATIVES OF PYRAZOL-4-YL-PYRROLO[2,3-d]PYRIMIDINES AND PYRROL-3-YL-PYRROLO[2,3-d]PYRIMIDINES AS JANUS KINASE INHIBITORS
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The present invention relates to N-(hetero)aryl-pyrrolidine derivatives of Formula I: which are JAK inhibitors, such as selective JAK1 inhibitors, useful in the treatment of JAK-associated diseases including, for example, inflammatory and autoimmune disorders, as well as cancer.
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Page/Page column 68
(2010/12/29)
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- 4-Piperidines and 3-pyrrolidines as dual serotonin and noradrenaline reuptake inhibitors: Design, synthesis and structure-activity relationships
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Single enantiomer [(aryloxy)(pyridinyl)methyl]piperidine and pyrrolidine derivatives 5-9 are inhibitors of monoamine reuptake. Structure-activity relationships established that monoamine reuptake inhibition are functions of amine, pyridine isomer, aryloxy ring substitution and stereochemistry. Consequently, selective NRIs, selective SRIs, dual SNRIs and triple SNDRIs were all identified. Dual SNRIs 5l-a and 9c were evaluated in additional pharmacology and pharmacokinetic studies as representative examples from this series.
- Fish, Paul V.,Andrews, Mark D.,Jonathan Fray,Stobie, Alan,Wakenhut, Florian,Whitlock, Gavin A.
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scheme or table
p. 2829 - 2834
(2010/03/03)
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- SPIRO CONDENSED PIPERIDNES AS MODULATORS OF MUSCARINIC RECEPTORS
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The present invention relates to modulators of muscarnic receptors of formula (I). The present invention also provides impositions comprising such modulators, and methods therewith for treating muscarinic receptor mediated diseases.
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- ANTITHROMBOTIC ETHERS
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This application relates to a compound of formula I (or a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug thereof) as defined herein, pharmaceutical compositions thereof, and its use as an inhibitor of factor Xa and/or thrombin, as well as a process for its preparation and intermediates therefor (I).
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- 3-pyrrolidinyloxy-3'-pyridyl ether compounds useful for controlling chemical synaptic transmission
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A series of 3-pyrrolidinyloxy-3′-pyridyl ether compounds, a method for selectively controlling neurotransmitter release in mammals using these compounds, and pharmaceutical compositions including these compounds. Preferred compounds are 3-pyrrolidinylmethoxy-3′-(5′-and/or 6′-substituted) pyridyl ethers.
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- Synthesis and serotonergic activity of 3-[2-(pyrrolidin-1- yl)ethyl]indoles: Potent agonists for the h5-HT(1D) receptor with high selectivity over the h5-HT(1B) receptor
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The design, synthesis, and biological evaluation of a novel series of 3- [2-(pyrrolidin-1-yl)ethyl]-indoles with excellent selectivity for h5-HT(1D) (formerly 5-HT(1Dα)) receptors over h5-HT(1B) (formerly 5-HT(1Dβ)) receptors are described. Clinically effective antimigraine drugs such as Sumatriptan show little selectivity between h5-HT(1D) and h5-HT(1B) receptors. The differential expression of h5-HT(1D) and h5-HT(1B) receptors in neural and vascular tissue prompted an investigation of whether a compound selective for the h5-HT(1D) subtype would have the same clinical efficacy but with reduced side effects. The pyrrolidine 3b was initially identified as having 9-fold selectivity for h5-HT(1D) over h5-HT(1B) receptors. Substitution of the pyrrolidine ring of 3b with methylbenzylamine groups gave compounds with nanomolar affinity for the h5-HT(1D) receptor and 100-fold selectivity with respect to h5-HT(1B) receptors. Modification of the indole 5-substituent led to the oxazolidinones 24a,b with up to 163-fold selectivity for the h5-HT(1D) subtype and improved selectivity over other serotonin receptors. The compounds were shown to be full agonists by measurement of agonist-induced [35S]GTPγS binding in CHO cells expressed with h5-HT receptors. This study suggests that the h5-HT(1D) and h5-HT(1B) receptors can be differentiated by appropriate substitution of the ligand in the region which binds to the aspartate residue and reveals a large binding pocket in the h5-HT(1D) receptor domain which is absent for the h5-HT(1B) receptor. The compounds described herein will be important tools to delineate the role of h5-HT(1D) receptors in migraine.
- Sternfeld, Francine,Guiblin, Alexander R.,Jelley, Richard A.,Matassa, Victor G.,Reeve, Austin J.,Hunt, Peter A.,Beer, Margaret S.,Heald, Anne,Stanton, Josephine A.,Sohal, Bindi,Watt, Alan P.,Street, Leslie J.
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p. 677 - 690
(2007/10/03)
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