- Synthesis method of 3-aminopyrrolidine dihydrochloride
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The invention discloses a synthetic method of 3-aminopyrrolidine dihydrochloride. The synthetic method comprises the following steps: preparing benzyl-(3-ethoxy-3-alkenyl)-(1-vinyl ethoxy methyl) amine liquid; preparation of a 1-benzyl-3-pyrrolidone solution; preparation of a 1-benzyl-3-aminopyrrolidine solution; preparing a 1-benzyl-3-aminopyrrolidine salt; preparing a 3-aminopyrrolidine solution; the yield and purity of the 3-aminopyrrolidine dihydrochloride are improved by controlling the activity of the reaction main materials of each part in a segmented manner and carrying out a directional hydrogenation manner.
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- Discovery and Biological Evaluation of N-Methyl-pyrrolo[2,3- b]pyridine-5-carboxamide Derivatives as JAK1-Selective Inhibitors
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Janus kinase 1 (JAK1) plays a key role in most cytokine-mediated inflammatory and autoimmune responses through JAK/STAT signaling; thus, JAK1 inhibition is a promising therapeutic strategy for several diseases. Analysis of the binding modes of current JAK inhibitors to JAK isoforms allowed the design of N-alkyl-substituted 1-H-pyrrolo[2,3-b] pyridine carboxamide as a JAK1-selective scaffold, and the synthesis of various methyl amide derivatives provided 4-((cis-1-(4-chlorobenzyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (31g) as a potent JAK1-selective inhibitor. In particular, the (S,S)-enantiomer of 31g (38a) exhibited excellent potency for JAK1 and selectivity over JAK2, JAK3, and TYK2. On investigating the effect of 31g on hepatic fibrosis, it was found that it reduces the proliferation and fibrogenic gene expression of TGF-β-induced hepatic stellate cells (HSCs). Specifically, 31g significantly inhibited TGF-β-induced migration of HSCs at 0.25 μM in wound-healing assays.
- Park, Eunsun,Lee, Sun Joo,Moon, Heegyum,Park, Jongmi,Jeon, Hyeonho,Hwang, Ji Sun,Hwang, Hayoung,Hong, Ki Bum,Han, Seung-Hee,Choi, Sun,Kang, Soosung
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p. 958 - 979
(2021/02/01)
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- The identification and use of robust transaminases from a domestic drain metagenome
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Transaminases remain one of the most promising biocatalysts for use in chiral amine synthesis, however their industrial implementation has been hampered by their general instability towards, for example, high amine donor concentrations and organic solvent content. Herein we describe the identification, cloning and screening of 29 novel transaminases from a household drain metagenome. The most promising enzymes were fully characterised and the effects of pH, temperature, amine donor concentration and co-solvent determined. Several enzymes demonstrated good substrate tolerance as well as an unprecedented robustness for a wild-type transaminase. One enzyme in particular readily accepted IPA as an amine donor giving the same conversion with 2-50 equivalents, as well as being tolerant to a number of co-solvents, and operational in up to 50% DMSO-a characteristic as yet unobserved in a wild-type transaminase. This work highlights the value of using metagenomics for biocatalyst discovery from niche environments, and here has led to the identification of one of the most robust native transaminases described to date, with respect to IPA and DMSO tolerance.
- Leipold, Leona,Dobrijevic, Dragana,Jeffries, Jack W.E.,Bawn, Maria,Moody, Thomas S.,Ward, John M.,Hailes, Helen C.
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- HETEROARYL COMPOUNDS AND THEIR USE AS MER INHIBITORS
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Compounds of formula (I) [Formula should be inserted here] and a pharmaceutically acceptable salt thereof, wherein A, R1, R2, R3, R4, R5, R6, R7, R24, X, L, n and p are as defined in the specification, are useful for treating or preventing Mer tyrosine kinase receptor modulated disease or conditions. Also described are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.
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Paragraph 1126; 1944
(2018/04/27)
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- Exploring Derivatives of Quinazoline Alkaloid l-Vasicine as Cap Groups in the Design and Biological Mechanistic Evaluation of Novel Antitumor Histone Deacetylase Inhibitors
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l-Vasicine is a quinazoline alkaloid with an electron dense ring and additional functionalities in its structure. Employing target oriented synthesis (TOS) based on in silico studies, molecules with significant docking scores containing different derivatives of l-vasicine as caps were synthesized. Interestingly, one molecule, i.e., 4a, which contained 3-hyroxypyrrolidine as a cap group and a six carbon long aliphatic chain as a linker was found to inhibit HDACs. 4a showed more specificity toward class I HDAC isoforms. Also 4a was found to be less cytotoxic toward normal cell lines as compared to cancer cell lines. 4a inhibited cancer cell growth and induced cell death by various mechanisms. However, 4a was found to induce cell death independent of ROS generation, and unlike many natural product based HDAC inhibitors, 4a was found to be nontoxic under in vivo conditions. Importantly, we for the first time report the possibility of using a 3-hydroxypyrrolidine cap for the synthesis of HDAC inhibitors with good potency.
- Ahmad, Mudassier,Aga, Mushtaq A.,Bhat, Javeed Ahmad,Kumar, Brijesh,Rouf, Abdul,Capalash, Neena,Mintoo, Mubashir Javeed,Kumar, Ashok,Mahajan, Priya,Mondhe, Dilip Manikrao,Nargotra, Amit,Sharma, Parduman Raj,Zargar, Mohmmad Afzal,Vishwakarma, Ram A.,Shah, Bhahwal Ali,Taneja, Subhash Chandra,Hamid, Abid
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p. 3484 - 3497
(2017/05/05)
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- A protection strategy substantially enhances rate and enantioselectivity in ω-transaminase-catalyzed kinetic resolutions
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The kinetic resolution of 3-aminopyrrolidine (3AP) and 3-aminopiperidine (3APi) with ω-transaminases was facilitated by the application of a protecting group concept. 1-N-Cbz-protected 3-aminopyrrolidine could be resolved with >99% ee at 50% conversion, the resolution of 1-N-Boc-3-aminopiperidine yielded 96% ee at 55% conversion. The reaction rate was up to 50-fold higher by using protected substrates. Most importantly, enantioselectivity increased remarkably after carbamate protection compared to the unprotected substrates (86 vs. 99% ee). Surprisingly, benzyl protection of 3AP had no influence on enantioselectivity. A possible explanation for this observation could be the different flexibility of the benzyl- or carbamate-protected 3AP as confirmed by NMR spectroscopy.
- Hoehne, Matthias,Robins, Karen,Bornscheuer, Uwe T.
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body text
p. 807 - 812
(2009/04/10)
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- PROCESS FOR PRODUCING NITROGENOUS HETEROCYCLIC COMPOUND
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A nitrogenous heterocyclic compound such as 3-aminopyrrolidine derivative is produced by hydrogenolysis of an N-substituted nitrogenous heterocyclic compound with normal pressure hydrogen in a water-based solvent in presence of a catalyst. In the case an optically active 1-substituted-3-aminopyrrrolidine derivative is used as a raw material, an optically active 3-aminopyrrolidine derivative can be obtained as a product practically without racemination.
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Page/Page column 10
(2010/11/08)
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- 1-SUBSTITUTED-3-PYRROLIDINE DERIVATIVES AS MUSCARINIC RECEPTOR ANTAGONISTS
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This invention generally relates to the derivatives of 1 -substituted-3 -pyrroli dines having the structure of Formula (I): The compounds of this invention can function as..muscarinic receptor antagonists, and can be used for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems mediated through muscarinic receptors. The invention also relates to a process for the preparation of the compounds of the present invention. pharmaceutical compositions containing the compounds of the present invention and the methods for treating the diseases mediated through muscarinic receptors.
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- Method of heightening optical purity of 1-benzyl-3-aminopyrrolidine and salt for used therein
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The present invention provides a method to improve the optical purity of 1-benzyl-3-aminopyrrolidine having a low optical purity using an inexpensive agent via a simple procedure. The present invention provides a method for improving the optical purity of 1-benzyl-3-aminopyrrolidine including the steps of converting 1-benzyl-3-aminopyrrolidine into an equimolar salt with an optically inactive acid, and recovering the salt as crystals. The present invention also provides a salt of 1-benzyl-3-aminopyrrolidine that is used in the method.
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- Chemo-enzymatic preparation of chiral 3-aminopyrrolidine derivatives
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A new simple method for the enantioselective enzymatic hydrolysis of N-protected D-asparagine esters suitable for the use on the preparative scale is presented. Due to major obstacles observed under conventional reaction conditions - racemization of the retained ester and a strong enzyme inactivation - a comparatively low pH together with an organic co-solvent had to be employed. Under these conditions, nearly all tested proteases demonstrated good activity and excellent enantioselectivity giving access to the corresponding D-esters and L-asparagines in high optical purities (>95% ee) and good chemical yields (>40%). From the unnatural D-asparagine derivative, sequential cyclization, selective deprotection and reduction yielded efficiently benzyl protected (R)-3-aminopyrrolidine, a homo-chiral building block utilized in numerous drug candidates.
- Iding, Hans,Wirz, Beat,Rogers-Evans, Mark
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p. 647 - 653
(2007/10/03)
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- Stereocontrolled dopamine receptor binding and subtype selectivity of clebopride analogues synthesized from aspartic acid
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Employing the achiral 4-aminopiperidine derivative clebopride as a lead compound, chiral analogues were developed displaying dopamine receptor binding profiles that proved to be strongly dependent on the stereochemistry. Compared to the D1 receptor, the t
- Einsiedel, Juergen,Weber, Klaus,Thomas, Christoph,Lehmann, Thomas,Huebner, Harald,Gmeiner, Peter
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p. 3293 - 3296
(2007/10/03)
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- Tetracyclic benzimidazole derivatives and combinatorial libraries thereof
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The present invention relates to novel tetracyclic benzimidazole derivative compounds of the following formula: wherein R1to R10have the meanings described in here. The invention further relates to combinatorial libraries containing two or more such compounds, as well as methods of preparing tetracyclic benzimidazole derivative compounds.
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- Methods for making optically active 3-aminopyrrolidine-2,5-dione derivative and optically active 3-aminopyrrolidine derivative
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A method for making an optically active 3-aminopyrrolidine-2,5-dione derivative represented by the formula (3) includes cyclizing an optically active asparagine ester derivative represented by the formula (1) or (2), or an acid salt thereof. A method for making an optically active 3-aminopyrrolidine derivative represented by the formula (9) includes reducing the optically active 3-aminopyrrolidine-2,5-dione derivative represented by the formula (3). A method for making an optically active 3-aminopyrrolidine derivative includes hydrogenolyzing the optically active 3-aminopyrrolidine derivative represented by the formula (9).
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Page column 13
(2008/06/13)
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- Process for producing 1H-3-aminopyrrolidine and derivatives thereof
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A process for producing 1H-3-aminopyrrolidine and derivatives thereof is disclosed. The process is especially useful for producing optically active 1H-3-aminopyrrolidine and derivatives thereof and in this case comprises reacting an optically active amino-protected aspartic anhydride represented by the formula (1) with a primary amine represented by the formula R'NH2, subjecting the reaction product to cyclodehydration to obtain an optically active 1-aralkyl-3-(protected amino)pyrrolidine-2,5-dione compound represented by the formula (2), subsequently eliminating the protective group from the 3-position amino group of the compound represented by the formula (2) to obtain an optically active 1-aralkyl-3-aminopyrrolidine-2,5-dione compound represented by the formula (3), reducing the carbonyl groups of the compound represented by the formula (3) to obtain either an optically active 1-aralkyl-3-aminopyrrolidine compound represented by the formula (4) or a salt thereof with a protonic acid, and then subjecting the compound represented by the formula (4) or the salt thereof to hydrogenolysis to obtain an optically active 1H-3-aminopyrrolidine or a protonic acid salt thereof.
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- Methods for making optically active 3-aminopyrrolidine-2,5-dione derivative and optically active 3-aminopyrrolidine derivative
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A method for making an optically active 3-aminopyrrolidine-2,5-dione derivative represented by the formula (3) includes cyclizing an optically active asparagine ester derivative represented by the formula (1) or (2) or an acid salt thereof. The optically active 3-aminopyrrolidine-2,5-dione derivative represented by the formula (3) may be reduced to form an optically active 3-aminopyrrolidine derivative represented by the formula (9). When, in the formula (9), R1 is an unsubstituted or substituted benzyl group, the compound may be hydrogenated to obtain the corresponding 1-unsubstituted compound in which R1 is hydrogen.
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- Process for producing 1H-3-aminopyrrolidine and derivatives thereof
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A process for producing 1H-3-aminopyrrolidine and derivatives thereof is disclosed. The process is especially useful for producing optically active 1H-3-aminopyrrolidine and derivatives thereof and in this case comprises reacting an optically active amino
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- Synthesis and structure-activity relationships of naphthamides as dopamine D3 receptor ligands
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A series of naphthamides were synthesized, and the affinities of these compounds were determined for dopamine D2 and D3 receptors using radioligand binding techniques. The naphthamide compounds that were prepared include N-(1- alkylp
- Huang,Luedtke,Freeman,Wu,Mach
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p. 1815 - 1826
(2007/10/03)
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- A convenient route to 1-benzyl 3-aminopyrrolidine and 3-aminopiperidine
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1-Benzyl 3-aminopyrrolidine 1 and 1-benzyl 3-aminopiperidine 2 were prepared rapidly mainly in aqueous conditions in 55 and 75% yields, respectively, on a multi-gram scale starting from inexpensive and commercially available starting materials. The key step involved the Curtius rearrangement mediated by sodium nitrite and trifluoroacetic acid of the appropriate acylhydrazides. All the reactions (except LAH reductions) were performed in water.
- Jean, Ludovic,Baglin, Isabelle,Rouden, Jacques,Maddaluno, Jacques,Lasne, Marie-Claire
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p. 5645 - 5649
(2007/10/03)
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- Process for making 3-amino-pyrolidine derivatives
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The invention is concerned with a process for making a compound of formula STR1 wherein R1 is hydrogen, alkyl, cyclo-alkyl, alkenyl, aryl or an amino protecting group; and R2, R3 each independently is hydrogen, alkyl, cyclo-alkyl, alkenyl or aryl; by reacting a compound of the formula STR2 wherein X is a protected hydroxy group; with R1 NH2 to form a compound of formula STR3 wherein X and R1 are described herein above; and then reacting the compound of formula III with R2 R3 NH under pressure to form the compound of formula I. These compounds are valuable intermediates useful in making cephalosporin derivatives.
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- An efficient conversion of chiral α-amino acids to enantiomerically pure 3-amino cyclic amines
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Enantiomerically pure 3-amino cyclic amines such as 3-amino pyrrolidine, 3-amino piperidine, and 2,3,4,5,6,7-hexahydro-1H-azepine have been synthesized in high yields from the optically active natural α-amino acids such as L-aspartic acid, L-glutamic acid, L-2-aminoadipic acid, and their enantiomers.
- Moon, Sung-Hwan,Lee, Sujin
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p. 3919 - 3926
(2007/10/03)
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- INDOL DERIVATIVES USEFUL FOR THE TREATMENT OF MIGRAINE, COMPOSITION AND UTILIZATION
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Indole derivatives having the Formula (I) wherein R1 is H, alkyl or acyl group; R2 is H, halogen or alkyl, hydroxy, alkoxy; ciano, carboxamide, carboxyl, alkoxicarbonyl, phenyl, phenyloxy or a group -(CH2)n-R6, (n=1-3), and R6 is a group ciano, nitro, phenyl, carboxyl, -CO2R7; -CONR7R8; -SO2NR7R8; -COR7; -SO2R7, R7 and R8 being H or alkyl; R7 and R8, together with N, can form a cycle of 4-7 links; R3, R4 and R5 are H, halogen or a group alkyl, phenyl, substituted phenyl, hydroxy, alcoxy, phenyloxy or benziloxy; NR11R12 is H or a group ciano, nitro, carboxyl, alcoxycarbonyl, carboxamido or a group R3; A is an alkyliden group -(CH2)-m, (m = 1-5), or alkenyl group; B is a piperazinoring (a), aminopyrrolidinoring (b); pyrrolidinamino ring (c); piperidinoring (d) or ethylendiamino -NR9-CH2-CH2-NR10-, R9 and R10 being H or an alkyl group. The compounds are useful for the treatment of migraine.
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- Process for the manufacture of (S)-3-amino-1-substituted-pyrrolidines
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A novel process for preparing a stereospecific (S)-3-amino-1-substituted pyrrolidine used as a key intermediate in preparing quinolone and naphthyridone antibacterial agents where the 7-position is occupied with a sterospecific 3-amino-pyrrolidine side chain is described starting from inexpensive L-aspartic acid. L-aspartic acid is converted to the desired (S)-3-aminopyrrolidine via a novel, high yield transformation of a substituted aziridine.
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- Process for preparing 3-amino-1-benzylpyrrolidines
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A process for preparing a 3-amino-1-benzyl-pyrrolidine of the formula STR1 in which R1 and R2 each independently is H or alkyl, and Ph is phenyl, comprising reacting a 1-benzyl-Δ3 -pyrroline-2,5-dione of the formula STR2 in which R3 and R4 each independently is H or alkyl, with a nitrogen nucleophile of the formula in which R5 is H, benzyl, naphthylmethyl or phenyl-CHR6, and R6 is C1 -C6 -alkyl or phenyl, to give an optionally substituted 3-amino-1-benzylpyrrolidine-2,5-dione of the formula STR3 and, if R5 ≠H, the protecting group R5 is subsequently cleaved off to give a 3-amino-1-benzylpyrrolidine-2,5-dione of the formula STR4 and completely reducing the carbonyl groups to form the 3-amino-1-benzylpyrrolidine of the formula (I).
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- Asymmetric Synthesis and Properties of the Enantiomers of the Antibacterial Agent 7-(3-Aminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic Acid Hydrochloride
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Compound 1 is a potent member of the quinoloecarboxylic acid class of antibacterial agents and is currently undergoing clinical evaluation.We have developed efficient asymmetric syntheses of the enantiomers of this agent.The S-(+) enantiomer 1a is 1-2 log2 dilutions more active than the R-(-) enantiomer 1b against aerobic bacteria and 1-2 or more log2 dilutions more active against anaerobic bacteria in vitro.The enantiomer 1a shows significantly better in vivo activity in a Pseudomonas aeruginosa mouse protection model compared to racemic 1.Coupled with the improved solubility profile of 1a relative to racemic material, these features may be of practical significance from a clinical standpoint.
- Rosen, Terry,Chu, Daniel T. W.,Lico, Isabella M.,Fernandes, Prabhavathi B.,Shen, Linus,et al.
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p. 1586 - 1590
(2007/10/02)
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