- X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson’s Disease
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Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson’s disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1H-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to23, which manifested IC50values of 0.64 and 0.04 μM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice.23showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar,23likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood.
- Ning, Xiang-Li,Li, Yu-Zhi,Huo, Cui,Deng, Ji,Gao, Cheng,Zhu, Kai-Rong,Wang, Miao,Wu, Yu-Xiang,Yu, Jun-Lin,Ren, Ya-Li,Luo, Zong-Yuan,Li, Gen,Chen, Yang,Wang, Si-Yao,Peng, Cheng,Yang, Ling-Ling,Wang, Zhou-Yu,Wu, Yong,Qian, Shan,Li, Guo-Bo
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p. 8303 - 8332
(2021/06/30)
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- Compound, preparation method thereof, pharmaceutical composition and application of compound
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The invention discloses a compound, a preparation method thereof, a pharmaceutical composition and application of the compound. The compound I, and a stereoisomer or a pharmacologically acceptable salt thereof can serve as a CDK7 kinase inhibitor, are high in inhibition activity, and can be used for treatment of various malignant tumors.
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Paragraph 0315; 0319-0321
(2020/01/03)
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- COMPOUNDS, COMPOSITIONS AND METHODS FOR SYNTHESIS
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The present disclosure, among other things, provides technologies for synthesis, including reagents and methods for stereoselective synthesis. In some embodiments, the present disclosure provides compounds useful as chiral auxiliaries. In some embodiments, the present disclosure provides reagents and methods for oligonucleotide synthesis. In some embodiments, the present disclosure provides reagents and methods for chirally controlled preparation of oligonucleotides. In some embodiments, technologies of the present disclosure are particularly useful for constructing challenging internucleotidic linkages, providing high yields and stereoselectivity.
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Paragraph 00663; 00664; 00667; 00668; 00691; 00698; 00699
(2019/01/10)
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- Protecting-Group-Directed Regio- and Stereoselective Oxymercuration-Demercuration: Synthesis of Piperidine Alkaloids Containing 1,2- and 1,3-Amino Alcohol Units
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An efficient synthesis of naturally occurring 1,2- and 1,3-amino alcohol unit containing 2-substituted piperidine alkaloids and their analogues has been developed from l -pipecolinic acid. The protocol describes the regio- and stereoselective oxymercuration-demercuration of 2-alkenyl piperidines based on protecting groups to give piperidine alkaloids as a key step.
- Bugde, Sandesh T.,Volvoikar, Prajesh S.,Tilve, Santosh G.
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p. 1113 - 1122
(2017/12/06)
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- As hepatitis c inhibitor spiro compound and its use in medicine
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The invention provides a spiro compound serving as a hepatitis c inhibitor and application thereof in a medicine. The compound is a compound as shown in a formula (I) or a stereisomer, a geometric isomer, a tautomer, nitric oxide, an aquo-complex, a solvate, a metabolite, pharmaceutically acceptable salt or prodrug of the compound as shown in the formula (I). The invention also provides a pharmaceutical composition containing the compound, application of the compound and the pharmaceutical composition in inhibition of HCV (Hepatitis C Virus) copy and HCV virus protein, as well as the application of the compound and the pharmaceutical composition in prevention, handling, treatment or relieving of HCV infection or hepatitis c disease for a patient. The formula I is as shown in the specification.
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Paragraph 1195; 1199; 1200
(2017/12/28)
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- COMPOUNDS AND USE FOR TREATING CANCER
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The present invention relates to certain 2,4-disubstituted quinoline derivatives, to their therapy, as well as to pharmaceutical compositions comprising said compounds. More specifically the invention relates to certain 2,4-disubstituted quinoline derivatives or pharmaceutical compositions comprising said compounds for the treatment of cancers characterized by overactive Ras and/or Rac or signalling pathway.
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- Discovery and Total Synthesis of Streptoaminals: Antimicrobial [5,5]-Spirohemiaminals from the Combined-Culture of Streptomyces nigrescens and Tsukamurella pulmonis
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A series of lipidic spirohemiaminals, designated streptoaminals, is reported. These were discovered by surveying the unique molecular signatures identified in the mass spectrometry data of the combined-culture broth of Streptomyces nigrescens HEK616 and T
- Sugiyama, Ryosuke,Nishimura, Shinichi,Ozaki, Taro,Asamizu, Shumpei,Onaka, Hiroyasu,Kakeya, Hideaki
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p. 10278 - 10282
(2016/08/24)
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- Benzimidazole-2-piperazine compound, its pharmaceutical composition and its preparation and use
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The invention relates to a benzimidazole-2-piperazine derivative and a preparing method and application of the benzimidazole-2-piperazine derivative in medicine, in particular to a novel benzimidazole-2-piperazine derivative shown in the general formula (I), a preparing method of the derivative, a pharmaceutical composition containing the derivative and application of the derivative serving as a therapeutic agent, especially serving as a poly (ADP-ribose) polymerase (PARP) inhibitor. In the general formula (I), R refers to hydrogen or halogen, G refers to carbonyl or methylene, m is 1-2, n is 1-3, and Q refers to hydrogen or C1-C4 alkyl. When X is methylene and Y is NR1 or methylene, X is NR1; R1 refers to hydrogen, C1-C6 alkyl, benzyl, COR2 or SO2R2; R2 refers to the following groups which are not substituted or groups substituted by 1-3 substituent groups, including C1-C6 alkyl, C3-C8 naphthenic base, phenyl, benzyl, naphthyl and C5-C10 aromatic heterocycle base, heterocycle in the C5-C10 aromatic heterocycle base comprises 1-3 heteroatoms selected from N, O and S, and the substituent groups are selected from the following atoms or groups of C1-C6 alkyl, C1-C6 alkoxy, halogen, amidogen, nitryl, sulfydryl, hydroxyl, cyanogroup and trifluoromethyl. The general formula (I) is shown in the specification.
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Paragraph 0209; 0439; 0442; 0443
(2016/10/20)
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- Design and synthesis of fused tetrahydroisoquinoline-iminoimidazolines
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In the aim of identifying new privileged structures, we describe the 5-steps synthesis of cyclic guanidine compounds "tetrahydroisoquinoline-iminoimidazolinesg" derived from tetrahydroisoquinoline-hydantoin core. In order to evaluate this new minimal structure and the impact of replacing a carbonyle by a guanidine moiety, their affinity towards adenosine receptor A2A was evaluated and compared to those of tetrahydroisoquinoline-hydantoin compounds.
- Moas-Héloire, Valeria,Renault, Nicolas,Batalha, Vania,Arias, Angela Rincon,Marchivie, Mathieu,Yous, Said,Deguine, Noémie,Buée, Luc,Chavatte, Philippe,Blum, David,Lopes, Luisa,Melnyk, Patricia,Agouridas, Laurence
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- A strategy for complex dimer formation when biomimicry fails: Total synthesis of ten coccinellid alkaloids
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Although dimeric natural products can often be synthesized in the laboratory by directly merging advanced monomers, these approaches sometimes fail, leading instead to non-natural architectures via incorrect unions. Such a situation arose during our studies of the coccinellid alkaloids, when attempts to directly dimerize Natures presumed monomeric precursors in a putative biomimetic sequence afforded only a non-natural analogue through improper regiocontrol. Herein, we outline a unique strategy for dimer formation that obviates these difficulties, one which rapidly constructs the coccinellid dimers psylloborine A and isopsylloborine A through a terminating sequence of two reaction cascades that generate five bonds, five rings, and four stereocenters. In addition, a common synthetic intermediate is identified which allows for the rapid, asymmetric formal or complete total syntheses of eight monomeric members of the class.
- Sherwood, Trevor C.,Trotta, Adam H.,Snyder, Scott A.
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supporting information
p. 9743 - 9753
(2014/07/22)
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- A stereospecific synthesis and unambiguous assignment of the absolute configuration of (-)-erythro-Mefloquine hydrochloride
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(-)-erythro-Mefloquine hydrochloride was synthesized stereospecifically from commercially available (S)-(-)-1-Boc-2-piperidinecarboxylic acid in four steps without disturbing the chiral center, and the absolute configuration of (-)-erythro-mefloquine hydrochloride was unambiguously determined as (11R,12S). (11S,12R)-(+)-erythro-Mefloquine hydrochloride was synthesized utilizing [(S,S)-TsDpen]Ru(p-cymene)Cl complexes-catalyzed enantioselective transfer hydrogenation of pyridyl ketone 7 as the key step, and the sense of asymmetric induction of 2-pyridyl ketone 7 is opposite to that of normal ketones in the transfer hydrogenation. Our results confirm the correctness of the determination of the absolute configuration by three physical chemistry methods, and, unbelievably, the erroneous assignments by all previous five asymmetric syntheses. Copyright
- Zhou, Gang,Liu, Xian,Liu, Xueying,Nie, Huifang,Zhang, Shengyong,Chen, Weiping
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supporting information
p. 3575 - 3580
(2014/01/06)
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- A concise diastereoselective approach to (+)-dexoxadrol, (-)-epi-dexoxadrol, (-)-conhydrine and (+)-lentiginosine from (-)-pipecolinic acid
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A new diastereoselective pathway for the total synthesis of (+)-dexoxadrol, first asymmetric synthesis of (-)-epi-dexoxadrol and formal synthesis of conhydrine and (+)-lentiginosine is presented using commercially available (-)-pipecolinic acid. The key reactions utilized are Sharpless asymmetric dihydroxylation and Wittig reaction. The paper further describes the study of effect of protecting groups on dihydroxylation of a terminal olefin in piperidine ring system.
- Bhat, Chinmay,Tilve, Santosh G.
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p. 10876 - 10883
(2014/01/06)
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- Henry-Nef reaction: A practical and versatile chiral pool route to 2-substituted pyrrolidine and piperidine alkaloids
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The paper describes the synergistic protocol developed by combinatorial Henry and Nef reaction for the synthesis of 2-substituted pyrrolidine and piperidine alkaloids containing 1,3-aminoketone and 1,3-amino alcohol units. The utility of the protocol is demonstrated by asymmetric synthesis of 12 natural products of which asymmetric synthesis of (-)-N-methylpelletierine is presented for the first time. The one-carbon homologation described also provides an alternate route for the synthesis of key intermediates homoprolinol and homopipecolinol used as synthetic precursors for several alkaloids and construction of β-amino acids from α-amino acids.
- Bhat, Chinmay,Tilve, Santosh G.
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p. 6129 - 6143
(2013/07/27)
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- L-Proline derived nitrogenous steroidal systems: An asymmetric approach to 14-azasteroids
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An efficient chiral pool approach using l-proline to access 14-azasteroids under mild reaction conditions has been described. The key step involves the intramolecular SN2′ cyclization reaction for the construction of critical C-ring in the nitrogen impregnated steroidal architectures bearing unsaturation at Δ9(11) position. In the endeavour to synthesize some new congeners, the remote electronic impact of the electron donating groups in A ring and heteroatoms like oxygen in B ring, on the propensity of C-ring cyclization was also observed.
- Singh, Ritesh,Panda, Gautam
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p. 19533 - 19544
(2013/10/22)
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- Enantioselective Synthesis of (+)-α-Conhydrine and (-)-Sedamine by L-ProlineCatalysed α-Aminooxylation
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An efficient organocatalytic approach to the enantioslective synthesis of two important piperidine alkaloids, namely (+)α-conhydrine (98% ee) and (-)-sedamine (95 % ee), by L-pro-line-catalysed α-aminooxylation of aldehydes has been developed. The strategy involves an intramolecular cyclization to construct the piperidine core.
- Shaikh, Tanveer Mahamadali,Sudalai, Arumugam
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experimental part
p. 3437 - 3444
(2010/08/20)
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- Inhibition of prolyl oligopeptidase with a synthetic unnatural dipeptide
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A new inhibitor, containing a linked proline-piperidine structure, for the enzyme prolyl oligopeptidase (POP) has been synthesised and demonstrated to bind covalently with the enzyme at the active site. This provides evidence that covalent inhibitors of P
- Racys, Daugirdas Tomas,Rea, Dean,Fueloep, Vilmos,Wills, Martin
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experimental part
p. 4775 - 4782
(2010/08/22)
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- A concise enantioselective synthesis of (+)-lentiginosine
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A high yielding enantioselective synthesis of the indolizidine alkaloid, (+)-lentiginosine, has been described based on asymmetric aza-Cope rearrangement and the l-proline catalyzed α-aminooxylation of aldehydes. The strategy also makes use of ring-closin
- Shaikh, Tanveer Mahamadali,Sudalai, Arumugam
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experimental part
p. 2287 - 2292
(2010/03/24)
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- Dynamic resolution of N-Boc-2-lithiopiperidine
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Dynamic thermodynamic resolution of N-Boc-2-lithiopiperidine is possible using a chiral ligand; the two enantiomers of this organolithium can be resolved with selectivities of up to 85: 15 from a selection of 26 chiral diamino-alkoxide ligands screened. The Royal Society of Chemistry.
- Coldham, Iain,Raimbault, Sophie,Chovatia, Praful T.,Patel, Jignesh J.,Leonori, Daniele,Sheikh, Nadeem S.,Whittaker, David T. E.
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experimental part
p. 4174 - 4176
(2009/03/11)
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- A concise synthesis of (±) and a total synthesis of (+)-epiquinamide
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A total synthesis of the quinolizidine alkaloid (+)-epiquinamide 1 has been achieved starting from (-)-pipecolinic acid 3. The key step is the highly diastereoselective addition of a TBDMS-protected propargyl alcohol to a chiral aldehyde derived from 3 to give erythro alkynol 19, which is then easily transformed into the desired bicyclic skeleton.
- Tong, Sok Teng (Amy),Barker, David
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p. 5017 - 5020
(2007/10/03)
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- The Baylis-Hillman reaction with chiral α-amino aldehydes under racemization-free conditions
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The Baylis-Hillman reaction with chiral α-amino aldehydes has been revisited. The reaction carried out under the influence of ultrasound avoids the aldehyde racemization almost completely, providing useful chiral substrates which can be used as starting materials for the synthesis of natural products. To demonstrate the synthetic applicability of these adducts, the easy preparation of a bicyclic lactam with an indolizidinic skeleton was accomplished. Georg Thieme Verlag Stuttgart.
- Coelho, Fernando,Diaz, Gaspar,Abella, Carlos A. M.,Almeida, Wanda P.
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p. 435 - 439
(2007/10/03)
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- Racemic and enantiopure 4-(piperidine-2′-yl)-pyridazines: Novel synthesis of anabasine-analogues with potential nicotinic acetylcholine receptor agonist activity - A new approach via Diels-Alder reaction with inverse electron demand
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A novel multistep synthesis of anabasine analogues bearing a bioisosteric pyridazine moiety instead of a pyridine nucleus in 2-position of the piperidine ring of the alkaloid is described. Starting materials are racemic 2-hydroxymethyl-piperidine, racemic pipecolic acid or (S)-(-)-piperidine-1,2-dicarboxylic-acid-1-tert-butyl ester. Key step of this synthetic approach is a Diels-Alder cycloaddition process with inverse electron demand utilizing diverse 1,2,4,5-tetrazines as electron-deficient dienes and the new racemic or enantiopure 2-(2′-methoxyethenyl)-piperidine as electron-rich dienophile. In this [4+2]-cycloadditions 1,2,4,5-tetrazines serve as synthons for introducing the pyridazine ring in the 2-position of the piperidine moiety.
- Stehl, Astrid,Seitz, Gunther,Schulz, Karen
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p. 1343 - 1354
(2007/10/03)
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- Aromatic amidine derivatives useful as selective thrombin inhibitors
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The present invention relates to a novel thrombin inhibitor which is effective even when orally administered. More specifically, the present invention relates to an aromatic amidine derivative represented by formula (I) and the salts thereof, which show potent selective inhibitory activity for thrombin in which (a), R, R1, R2, R3, A, W, Y and n are defined as described in the specification.
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- Synthesis and activity of 3-pyridylamine ligands at central nicotinic receptors
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A series of thirty 2-(3-pyridylaminomethyl)azetidine, pyrrolidine and piperidine analogues as nicotinic acetylcholine receptor (nAChR) ligands was explored. In general, pyrrolidinyl and many azetidinyl compounds were found to bind with enhanced affinity relative to the piperidines. In the three series, the parallel structural changes (stereochemistry, N-methylation and/or chloro substitution) do not consistently lead to parallel shifts in affinity. The more active compounds (K(i) affinity values ranging from 8.9 to 90 nM) were about as analgesic as nicotine in a tail-flick assay in mice after subcutaneous injections. (C) 2000 Editions scientifiques et medicales Elsevier SAS.
- Balboni, Gianfranco,Marastoni, Mauro,Merighi, Stefania,Borea, Pier Andrea,Tomatis, Roberto
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p. 979 - 988
(2007/10/03)
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- Enantioselective syntheses of 2-alkyl- and 2,6-dialkylpiperidine alkaloids: preparations of the hydrochlorides of (-)-coniine, (-)-solenopsin A, and (-)-dihydropinidine.
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[reaction: see text] Sequences of lithiation-substitution, enantioselective hydrogenation, and diastereoselective lithiation-substitution provide efficient highly enantioselective syntheses of 2-substituted and cis and trans 2,6-disubstituted piperidines.
- Wilkinson,Stehle,Beak
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p. 155 - 158
(2007/10/03)
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- Inhibitors of farnesyl-protein transferase
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The present invention comprises analogs of the CAAX motif of the protein Ras that is modified by farnesylation in vivo. These CAAX analogs inhibit farnesyl-protein transferase. Furthermore, these CAAX analogues differ from those previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.
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- Short syntheses of (S)-pipecolic acid, (R)-coniine, and (S)-δ-coniceine using biocatalytically-generated chiral building blocks
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The kinetic resolutions of both (±)-N-(benzyloxycarbonyl-2- (hydroxymethyl)piperidine [(±)-5] and (±)-N(tert-butoxycarbonyl)-2- (hydroxymethyl)piperidine [(±)-6] catalyzed by the enzyme acylase I from Aspergillus species (AA-I) afforded the chiral building blocks (S)-5 and (S)- 6, respectively; which were used for the syntheses of the title natural products and derivatives of (S)-pipecolic acid. The syntheses were short (2- 4 steps) and proceeded with satisfactory overall yield.
- Sanchez-Sancho, Francisco,Herradon, Bernardo
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p. 1951 - 1965
(2007/10/03)
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- Erste dynamische kinetische Enantiomerentrennung von α-Aminoaldehyden
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Stichworte: Asymmetrische Synthesen * Aminoaldehyde * Chirale Hilfsstoffe * Enantiomerentrennung * Horner-Wadsworth-Emmons-Reaktion
- Rein, Tobias,Kreuder, Reinhard,Zezschwitz, Paultheo von,Wulff, Christian,Reiser, Oliver
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p. 1099 - 1102
(2007/10/02)
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- Synthesis and in Vitro Characterization of Novel Amino Terminally Modified Oxotremorine Derivatives for Brain Muscarinic Receptors
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A series of novel 2-substituted acetylenic pyrrolidines and piperidines related to oxotremorine (1) were prepared and evaluated in vitro as muscarinic cholinergic agents at brain M1 and M2 receptors.One analogue, 3-(2-oxo-1-pyrrolidinyl)-1--1-propyne hydrogen oxalate (6a), was found to be a partial agonist producing a PI hydrolysis response at cortical M1 receptors approximately 3-fold larger than that produced by 1.The intrinsic activity profile of 6a at brain muscarinic receptors is similar to those of azetidine oxo analogue 2 and dimethylamino oxo analogue (3).All three compounds are partial M1 agonists and full M2 agonists; however, the profile of 6a in binding studies is significantly different.While 2 and 3 exhibit large M2 selectivities ranging between 8-fold to several hundred-fold, the binding profile of 6a shows almost no subtype selectivity.
- Garvey, David S.,Wasicak, James T.,Chung, John Y.-L.,Shue, Youe-Kong,Carrera, George M.,et al.
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p. 1550 - 1557
(2007/10/02)
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