- Total Synthesis of Malacidin A by β-Hydroxyaspartic Acid Ligation-Mediated Cyclization and Absolute Structure Establishment
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The development of novel antibiotics is critical to combating the growing emergence of drug-resistant pathogens. Malacidin A is a new member of the calcium-dependent antibiotic (CDAs) family with activity against antibiotic-resistant pathogens. Its mode of action is distinct from classical CDAs. However, the absolute structure of malacidin A has not been established. Herein, the total syntheses of malacidin A and its analogues are reported by a combination of Fmoc-based solid-phase peptide synthesis (SPPS) and β-hydroxyaspartic acid ligation-mediated peptide cyclization. The total synthesis enabled us to establish the absolute configuration of malacidin A, which is in agreement with those for natural malacidin A confirmed by advanced Marfey's analysis in our study.
- Brady, Sean F.,Chen, Sheng,Forelli, Nicholas,Li, Xuechen,Po, Kathy Hiu Laam,Shang, Zhuo,Sun, Zhenquan
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- Synthesis and evaluation of a (3R,6S,9S)-2-oxo-1-azabicyclo[4.3.0]nonane scaffold as a mimic of Xaa-trans-Pro in poly-l-proline type II helix conformation
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We describe the development of a small-molecule mimic of Xaa-trans-Pro dipeptide in poly-l-proline type II helix conformation, based upon a (3R,6S,9S)-2-oxo-1-azabicyclo[4.3.0]nonane core structure. Stereoselective synthesis of the mimic from l-pyroglutamic acid is achieved in twelve linear steps and 9.9% yield. Configurational and conformational analyses are conducted using a combination of 1H NMR spectroscopy, X-ray crystallography and circular dichroism spectroscopy; and evaluation of the mimic as a promising surrogate dipeptide, in a protein-protein interaction between the SH3 domain of human Fyn kinase (Fyn SH3) and peptidomimetics of its biological ligand, are conducted by 1H-15N HSQC NMR titration experiments.
- Aillard, Boris,Kilburn, Jeremy D.,Blaydes, Jeremy P.,Tizzard, Graham J.,Findlow, Stuart,Werner, J?rn M.,Bloodworth, Sally
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- A convenient and efficient synthesis of (2S,4R)- and (2S,4S)-4-methylglutamic acid
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Both enantiomerically pure (2S,4S)- and (2S,4R)-4-methylglutamic acids have been prepared in an overall 60% yield, by a convenient 7-step synthesis based on C-4 alkylation/epimerization of readily available (S)-pyroglutamic acid.
- Coudert, Elisabeth,Acher, Francine,Azerad, Robert
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- A versatile chiral pyrrolidine aldehyde building-block for synthesis and formal synthesis of ent-nakadomarin A
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A stable, simple to synthesise and versatile chiral aldehyde building-block has been developed, its reactivity in Wittig, Horner-Wadsworth-Emmons and Grignard reactions investigated, and its use is demonstrated in a highly efficient synthesis of an intermediate in Dixon's synthesis of nakadomarin A. Georg Thieme Verlag Stuttgart.
- Stockman, Robert A.,McDermott, Paul J.,Newton, Annabella F.,Magnus, Philip
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Read Online
- Synthesis of a new chiral amine: (S)-5,5-dimethyl-2-methoxymethyl-pyrrolidine
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The title compound, a potential 'quat' auxiliary,was prepared from (S)-glutamic acid derivatives like (S)-N-Benzyl-5-methoxymethyl-2-pyrrolidinone 1. Other routes starting from (S)-pyroglutamic acid in an attempt to bypass N-Aryl compounds like 1 were also tested, but have not rendered the expected results yet.
- Brena-Valle,Cruz-Almanza,Guadarrama-Morales
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Read Online
- Separation of pyrrolidine allylation products by diastereoselective enzymatic ester hydrolysis
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A multi-parallel enzyme screen has been used to identify potential catalysts for the selective hydrolysis of diastereomeric esters and then subsequently applied in their separation upon scaleup.
- Aggarwal, Varinder K.,Astle, Christopher J.,Iding, Hans,Wirz, Beat,Rogers-Evans, Mark
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Read Online
- Preparation of peptide-like bicyclic lactams via a sequential Ugi reaction - Olefin metathesis approach
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Bicyclic lactams, suitable for incorporation into conformationally restricted peptide mimics, can be synthesized by using olefinic starting materials for the Ugi multicomponent reaction, setting up an olefin metathesis reaction, that is easily carried out with the Grubbs catalyst. The influence of the different starting materials is evaluated. In addition, the utilization of chiral, nonracemic amines is described.
- Krelaus, Ralf,Westermann, Bernhard
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Read Online
- Oxidation of α-amino acids promoted by the phthalimide N-oxyl radical: A kinetic and product study
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A kinetic study of the hydrogen atom transfer (HAT) reaction from a series of N-Boc- or N-Acetyl-protected amino acids to the phthalimide N-oxyl radical (PINO) was carried out to obtain information about reactivity and selectivity patterns. With amino acids containing aliphatic side chains, the 2nd order rate constants are of the same order of magnitude, in agreement with a HAT process involving the Cα?H bond. Proline is the most reactive substrate suggesting that HAT process involves the Cδ?H bond instead of Cα?H bond. These results are confirmed by the product analysis of the aerobic oxidations of the corresponding N-Boc and N-Ac protected amino acids methyl esters promoted by N-hydroxyphthalimide. Comparison of our results with those reported for HAT reactions to other radical species indicates that PINO displays electrophilic characteristics that are intermediate between those observed for the more stable Br[rad] radical and the more reactive cumyloxyl radical.
- Ticconi, Barbara,Mazzonna, Marco,Lanzalunga, Osvaldo,Lapi, Andrea
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Read Online
- An cost-effective and safe process of L-cis-4,5-methanoproline amide, the key synthetic intermediate of saxagliptin, via an improved Simmons-Smith reaction
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L-cis-4,5-Methanoproline amide, a key intermediate of saxagliptin, was synthesized by an improved Simmons-Smith reaction. The zinc carbenoid was formed through Zn/CuBr and CH2I2, under the optimized condition, the title compound was gained with 68% yield and excellent diastereomeric selectivity (40:1 d.r.). The absence of the flammable and expensive ZnEt2 makes this procedure very attractive in large scale production.
- Ding, Ding,Pan, Xianhua,Yu, Wansheng,Li, Xiaojun,Chen, Suke,Liu, Feng
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Read Online
- Synthesis of (2S,3S)-[3-2H1]- and (2S,3R)-[2,3-2H2]-proline
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Discovery of conditions for intramolecular trapping of a ketene intermediate has led to an effective synthesis of samples of the amino acid proline which are stereospecifically labelled on the β-carbon. Since samples of stereospecifically labelled pyroglutamic acid derivatives are prepared in the route, other stereospecifically labelled, biologically important amino acids may be accessed by the synthesis.
- Dieterich,Young
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Read Online
- Enantiopure 5-CF3-Proline: Synthesis, Incorporation in Peptides, and Tuning of the Peptide Bond Geometry
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The straightforward synthesis of enantiopure 5-(R)-and 5-(S)-trifluoromethylproline is reported. The key steps are a Ruppert-Prakash reagent addition on l-pyroglutamic esters followed by an elimination reaction and a selective reduction. The solution-phase and solid-phase incorporation of this unprotected enantiopure fluorinated amino acid in a short peptide chain was demonstrated. Compared to proline, the CF3 group provides a decrease of the trans to cis amide bond isomerization energy and an increase of the cis conformer population.
- Sanchez, Clément A.,Gadais, Charlène,Chaume, Grégory,Girard, Sylvaine,Chelain, Evelyne,Brigaud, Thierry
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supporting information
p. 382 - 387
(2021/01/13)
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- Discovery of SY-5609: A Selective, Noncovalent Inhibitor of CDK7
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CDK7 has emerged as an exciting target in oncology due to its roles in two important processes that are misregulated in cancer cells: cell cycle and transcription. This report describes the discovery of SY-5609, a highly potent (sub-nM CDK7 Kd) and selective, orally available inhibitor of CDK7 that entered the clinic in 2020 (ClinicalTrials.gov Identifier: NCT04247126). Structure-based design was leveraged to obtain high selectivity (>4000-times the closest off target) and slow off-rate binding kinetics desirable for potent cellular activity. Finally, incorporation of a phosphine oxide as an atypical hydrogen bond acceptor helped provide the required potency and metabolic stability. The development candidate SY-5609 displays potent inhibition of CDK7 in cells and demonstrates strong efficacy in mouse xenograft models when dosed as low as 2 mg/kg.
- Alnemy, Sydney,Bradley, Michael J.,Chuaqui, Claudio,Ciblat, Stephane,Hamman, Kristin B.,Hu, Shanhu,Kabro, Anzhelika,Ke, Nan,Malojcic, Goran,Marineau, Jason J.,Mihalich, Janessa,Roy, Stephanie,Savinainen, Anneli,Schmidt, Darby,Waters, Nigel J.,Whitmore, Kenneth Matthew,Wilsily, Ashraf,Winter, Dana K.,Zahler, Robert
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- INHIBITORS OF NOROVIRUS AND CORONAVIRUS REPLICATION
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Compounds of Formula (I) and methods of inhibiting the replication of viruses in a biological sample or patient, of reducing the amount of viruses in a biological sample or patient, and of treating a virus infection in a patient, comprising administering to said biological sample or patient an effective amount of a compound represented by Formula (I), a compound of Table A or B or a pharmaceutically acceptable salt thereof.
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Paragraph 00463; 00470-00471
(2021/10/15)
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- INHIBITORS OF CYCLIN-DEPENDENT KINASE 7 (CDK7)
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The present invention provides various compositions, including compounds of Formula (I) or (la), or a species thereof, and pharmaceutically acceptable salts, solvates (e.g., hydrates), stereoisomer, tautomers, isotopic and other specified forms thereof. Also provided are methods (or uses) and kits involving the compounds or pharmaceutically acceptable compositions containing them for treating or preventing a disease (e.g., a proliferative disease such as cancer) in a subject. Administration of a compound or pharmaceutical composition described herein is expected to inhibit cyclin-dependent kinase 7 (CDK7), and thereby, induce apoptosis in tumor cells in the subject.
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Paragraph 124
(2020/05/28)
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- Palladium-Catalyzed Suzuki-Miyaura Reactions of Aspartic Acid Derived Phenyl Esters
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Transition-metal-catalyzed transformations of amino acids and peptides could provide a powerful method for their site-selective modification. Here, we report non-decarbonylative Pd-catalyzed Suzuki-Miyaura reactions of phenyl ester derivatives of aspartic acid to form aryl-amino ketones. These products are potentially important in the synthesis of pharmaceuticals, and our methodology represents a new route to access molecules of this type.
- Dardir, Amira H.,Hazari, Nilay,Miller, Scott J.,Shugrue, Christopher R.
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supporting information
p. 5762 - 5766
(2019/08/01)
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- Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic Properties
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Free fatty acid receptor 2 (FFA2/GPR43) is a receptor for short-chain fatty acids reported to be involved in regulation of metabolism, appetite, fat accumulation, and inflammatory responses and is a potential target for treatment of various inflammatory and metabolic diseases. By bioisosteric replacement of the central pyrrolidine core of a previously disclosed FFA2 agonist with a synthetically more tractable thiazolidine, we were able to rapidly synthesize and screen analogues modified at both the 2- and 3-positions on the thiazolidine core. Herein, we report SAR exploration of thiazolidine FFA2 agonists and the identification of 31 (TUG-1375), a compound with significantly increased potency (7-fold in a cAMP assay) and reduced lipophilicity (50-fold reduced clogP) relative to the pyrrolidine lead structure. The compound has high solubility, high chemical, microsomal, and hepatocyte stability, and favorable pharmacokinetic properties and was confirmed to induce human neutrophil mobilization and to inhibit lipolysis in murine adipocytes.
- Hansen, Anders H?jgaard,Sergeev, Eugenia,Bolognini, Daniele,Sprenger, Richard R.,Ekberg, Jeppe Hvidtfeldt,Ejsing, Christer S.,McKenzie, Christine J.,Rexen Ulven, Elisabeth,Milligan, Graeme,Ulven, Trond
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supporting information
p. 9534 - 9550
(2018/10/24)
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- INHIBITORS OF CYCLIN DEPENDNT KINASE 7 (CDK7)
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The present invention provides novel compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, melanoma, multiple myeloma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of cyclin-dependent kinase 7 (CDK7), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject.
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Paragraph 324
(2018/02/28)
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- Synthesis of Bicyclic and Tricyclic Chiral Guanidinium Salts by an Intramolecular Alkylation Approach
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Synthetic studies leading to three new types of chiral guanidinium scaffolds are described. Structures of interest include bicyclic guanidine derivatives with various substitution patterns around the guanidine core, as well as a highly rigid tricyclic scaffold. The challenging targets were accessed by application of mercury(II)-promoted guanylation of N-Boc-substituted thioureas and Ishikawa's desulfurative cyclization. In addition to our synthetic logics, a scalable synthesis of the tricyclic guanidinium salt is presented.
- Turo?kin, Aleksej,Raven, William,Selig, Philipp
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supporting information
p. 296 - 305
(2017/01/24)
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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 1140; 1145; 1146
(2017/12/28)
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- Debio-1143: Inhibitor of apoptosis protein (IAP) antagonist Cancer therapy
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Inhibitors of apoptosis proteins (IAPs) block caspases, modulate nuclear factor NF-êB signaling pathways and are involved in resistance to cancer therapies. Debio-1143, a mimetic of an endogenous IAP inhibitor (second mitochondriaderived activator of caspases [SMAC]), may help to overcome treatment resistance and has demonstrated antitumor activity in various cancer cell lines and xenograft models, alone or in combination with chemotherapy, radiotherapy or immunotherapies. So far, about 150 cancer patients have been enrolled in 5 registered early-phase clinical trials testing Debio-1143. Tolerability was acceptable even when the drug was used in combination therapies. In monotherapy, pharmacokinetics was linear, but varied considerably among patients in combination settings. High tumor penetration and on-target activity were consistently shown in patient surrogate tissues and tumor biopsies. Tumor responses to second-(or higher) line monotherapy in patients with various advanced cancers were rather weak, but currently followed approaches as an adjunct to existing cancer therapies look encouraging. Still, to identify ideal target populations and concomitant regimens remains challenging.
- Ray-Coquard,Bourhis,Delord,Vuagniaux,Zanna,Lu,Wang
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p. 745 - 755
(2018/03/21)
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- Synthetic method of Boc-L-Pyroglutamic acid methyl ester
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The invention discloses a synthetic method of Boc-L-Pyroglutamic acid methyl ester. The synthetic method comprises the following steps: dissolving L-pyroglutamic acid into methanol, adding a catalyst thionyl chloride and reacting, adding sodium bicarbonate to stop the reaction and generating methyl L-pyroglutamate; dissolving Methyl L-pyroglutamate into dichloromethane, adding a catalyst DMAP, adding di-tert-butyl dicarbonate in batches, and reacting to generate Boc-L-Pyroglutamic acid methyl ester. By using L-pyroglutamic acid as a raw material for preparation of Boc-L-Pyroglutamic acid methyl ester, the method has advantages of simple operation and low cost. The Boc-L-Pyroglutamic acid methyl ester prepared by the method has high yield, and purity can reach 99.8%. The product can meet quality requirements of the market. Therefore, the method is simple to operate, is convenient to prepare, is low-cost, is green and environment friendly, has no harsh reaction condition, and is suitable for large-scale industrial production.
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Paragraph 0041; 0042; 0043; 0044; 0045; 0046; 0047-0049
(2017/05/23)
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- A Catalyst Designed for the Enantioselective Construction of Methyl- and Alkyl-Substituted Tertiary Stereocenters
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Tertiary methyl-substituted stereocenters are present in numerous biologically active natural products. Reported herein is a catalytic enantioselective method for accessing these chiral building blocks using the Mukaiyama-Michael reaction between silyl ketene thioacetals and acrolein. To enable remote enantioface control on the nucleophile, a new iminium catalyst, optimized by three-parameter tuning and by identifying substituent effects on enantioselectivity, was designed. The catalytic process allows rapid access to chiral thioesters, amides, aldehydes, and ketones bearing an α-methyl stereocenter with excellent enantioselectivities, and allowed rapid access to the C4-C13 segment of (-)-bistramide A. DFT calculations rationalized the observed sense and level of enantioselectivity.
- Claraz, Aurlie,Sahoo, Gokarneswar,Berta, Dnes,Madarsz, dm,Ppai, Imre,Pihko, Petri M.
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supporting information
p. 669 - 673
(2016/02/27)
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- Flexible and modular syntheses of enantiopure 5-cis-substituted prolinamines from l-pyroglutamic acid
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A wide range (25 examples) of 5-cis-substituted prolinamines is prepared in five to ten steps starting from cheap l-pyroglutamic acid. Three routes, differing mainly in the order of introduction of the substituents at the 5-cis position, the pyrrolidine nitrogen atom, and the exocyclic amino function, are successfully developed.
- Prause, Felix,Kaldun, Johannes,Arensmeyer, Benjamin,Wennemann, Benedikt,Fr?hlich, Benjamin,Scharnagel, Dagmar,Breuning, Matthias
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supporting information
p. 575 - 586
(2015/02/19)
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- SPIRO COMPOUNDS AS HEPATITIS C VIRUS INHIBITORS
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Disclosed are spiro compounds of formula (I), or stereomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof. The compounds can be used to treat hepatitis C virus (HCV) infection or hepatitis C disease. Furthermore disclosed are pharmaceutical compositions containing the compounds and the method of using the compounds or pharmaceutical compositions in the treatment of HCV infection or hepatitis C disease.
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Paragraph 0636
(2015/11/09)
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- Bridged Ring compounds As Hepatitis C Virus (HCV) Inhibitors And Pharmaceutical Applications Thereof
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Provided herein is a compound having Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, which can be used for treating HCV infection or a HCV disorder. Also provided herein are pharmaceutical compositions comprising the compounds disclosed herein, which can be used for treating HCV infection or a HCV disorder.
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Paragraph 0748; 0753; 0754; 0755; 0756
(2015/03/28)
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- A new class of non-C2-symmetric ligands for oxidative and redox-neutral palladium-catalyzed asymmetric allylic alkylations of 1,3-diketones
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We report the discovery, synthesis, and application of a new class of non-C2-symmetric phosphoramidite ligands derived from pyroglutamic acid for use in both oxidative and redox-neutral palladium-catalyzed asymmetric allylic alkylations of 1,3-diketones. The resulting chiral products are typically obtained in high yield with good to excellent levels of enantioselectivity.
- Trost, Barry M.,Donckele, Etienne J.,Thaisrivongs, David A.,Osipov, Maksim,Masters, James T.
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supporting information
p. 2776 - 2784
(2015/03/04)
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- BRIDGED RING COMPOUNDS AS HEPATITIS C VIRUS (HCV) INHIBITORS AND PHARMACEUTICAL APPLICATIONS THEREOF
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Provided herein is a compound having Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, which can be used for treating HCV infection or a HCV disorder. Also provided herein are pharmaceutical compositions comprising the compounds disclosed herein, which can be used for treating HCV infection or a HCV disorder.
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Paragraph 00347
(2014/02/16)
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- FUSED RING COMPOUNDS AS HEPATITIS C VIRUS INHIBITORS, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
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Provided are fused tricyclic compounds effective to inhibit the function of the NS5A protein of formula (I), wherein X, X', Y, Y', A, A',Q1, Q2, R1-R4, X4, R5a, f and W are defined as in the description. Also provided herein are pharmaceutical compositions thereof, and uses in the manufacture of a medicament for treating HCV infection or a HCV disorder thereof.
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Paragraph 00353; 00355; 00487; 00489
(2014/06/23)
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- SPIRO RING COMPOUND AS HEPATITIS C VIRUS (HCV) INHIBITOR AND USES THEREOF FIELD OF THE INVENTION
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A compound of formula (I) or a stereoisomer, a geometric isomer. a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof is provided, which can be used for treating HCV infection or a HCV disorder. Also a pharmaceutical composition comprising the compound and the use of the compound and the pharmaceutical composition thereof are provided, which can also be used for treating HCV infection or a HCV disorder.
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Page/Page column 149; 150; 151
(2014/06/23)
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- BRIDGED RING COMPOUNDS AS HEPATITIS C VIRUS INHIBITORS, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
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Provided herein is a compound of formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, which can be used for treating HCV infection or a HCV disorder. Also provided herein are a pharmaceutical composition comprising the compound and the use of the compound and the pharmaceutical composition thereof, which can also be used for treating HCV infection or a HCV disorder.
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Page/Page column 118
(2014/09/16)
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- BICYCLIC AROMATIC CARBOXAMIDE COMPOUNDS USEFUL AS PIM KINASE INHIBITORS
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The present disclosure describes bicyclic aromatic carboxamide derivatives, as well as their compositions and methods of use. The compounds inhibit the activity of the Pim kinases, and are useful in the treatment of diseases related to the activity of Pim kinases including, e.g., cancer and other diseases.
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Paragraph 0681; 0682
(2014/07/23)
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- Methanesulfonic acid mediated cyclization and meyer-schuster rearrangement of γ-amino-ynones: Access to enantiopure pyrrolidine exocyclic vinylogous amides
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α- and β-Amino-ynones have been largely used to prepare heterocyclic rings in the presence of various electrophiles such as protic acids or gold(I). Herein we disclose the unprecedented formation of pyrrolidine exocyclic vinylogous amides, in place of the expected azepinones or piperidinones, starting from γ-amino-ynones derived from amino acids. The process involves a tandem 1,2-addition of the protected nitrogen to the carbonyl group followed by a Meyer-Schuster rearrangement, which efficiently afforded enantiopure pyrrolidine exocyclic vinylogous amides. The sequence is poorly catalyzed by gold salts, but proved to be very efficient in the presence of methanesulfonic acid. Copyright
- Vu, Huy-Dinh,Renault, Jacques,Roisnel, Thierry,Gouault, Nicolas,Uriac, Philippe
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p. 4506 - 4514
(2014/08/05)
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- THIAZOLECARBOXAMIDES AND PYRIDINECARBOXAMIDE COMPOUNDS USEFUL AS PIM KINASE INHIBITORS
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The present disclosure describes thiazole and pyridine carboxamide derivatives, their compositions and methods of use. The compounds inhibit the activity of the Pim kinases and are useful in the treatment of diseases related to the activity of Pim kinases including, e.g., cancer and other diseases.
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Paragraph 0820; 0821
(2014/07/23)
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- BICYCLIC PYRIDAZINE COMPOUNDS AS PIM INHIBITORS
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The invention relates to bicyclic compounds of formulas I and I', and salts thereof. In some embodiments, the invention relates to inhibitors or modulators of Pim-1 and/or Pim-2, and/or Pim-3 protein kinase activity or enzyme function. In still further embodiments, the invention relates to pharmaceutical compositions comprising compounds disclosed herein, and their use in the prevention and treatment of Pim kinase related conditions and diseases, preferably cancer.
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Page/Page column 84
(2012/11/13)
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- HEPATITIS C VIRUS INHIBITORS
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This disclosure concerns novel compounds of Formula (I) as defined in the specification and compositions comprising such novel compounds. These compounds are useful antiviral agents, especially in inhibiting the function of the NS5A protein encoded by Hepatitis C virus (HCV). Thus, the disclosure also concerns a method of treating HCV related diseases or conditions by use of these novel compounds or a composition comprising such novel compounds
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Page/Page column 143
(2012/04/10)
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- ANTIBIOTIC DRUG
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This invention relates to a malic acid salt of (3S, 5R)-7-[3-amino-5-methyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid. Also disclosed is a method of treating bacterial infection by an effective amount of this salt.
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Page/Page column 6
(2010/04/03)
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- Scale-up of trisodium [(3Β,5Β,12α)-3-[[4(S)-4-[bis[2- [bis[(carboxy-kO)methyl]aminokN] ethyl]amino-kN]-4-(carboxy-kO)-1-oxobutyl] amino]-12-hydroxycholan-24- oato(6-)]gadolinate(3-)], a Gd(III) complex under development as a contrast agent for MRI coronary angiography
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Process chemistry involved in the discovery and development routes to trisodium [(3Β,5Β,12α)-3-[[4(S)-4-[bis[2-[bis[(carboxykO) methyl]amino-kN]ethyl]amino-kN]-4-(carboxy-kO)-1-oxobutyl]- amino]-12- hydroxycholan-24-oato(6-)]gadolinate(3-)] (B22956/1) starting from L-glutamic acid and (3α,5Β,12α)-3,12-dihydroxycholan-24-oic acid is described. The best process is based on seven chemical steps and overcomes difficult purification protocols. Such process has been successfully implemented to prepare multikilogram batches of the target compound in 20% overall yield from (3α,5Β,12α)-3,12-dihydroxycholan-24-oic acid.
- Anelli, Pier Lucio,Brocchetta, Marino,Lattuada, Luciano,Manfredi, Giuseppe,Morosini, Pierfrancesco,Murru, Marcella,Palano, Daniela,Sipioni, Marco,Visigalli, Massimo
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experimental part
p. 739 - 746
(2010/04/22)
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- PHARMACEUTICAL COMPOSITIONS COMPRISING 2-METHOXY-5- (5-TRIFLUOROMETHYL-TETRAZOL-I-YL-BENZYL) - (2S-PHENYL-PIPERIDIN-3S-YL-)
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The present invention relates to pharmaceutical compositions comprising the NK1 receptor antagonist [2-Methoxy-5-(5-trifuoromethyl-tetrazol-1-yl)-benzyl]-(2S-phenyl- piperidin-3S-yl)-amine, or a pharmaceutically acceptable salt or solvate thereof, and a sodium channel blocker, as a combined preparation for simultaneous or sequential administration and to the use of such compositions in the treatment of certain disorders, including epilepsy, mood disorders and pain.
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Page/Page column 20
(2008/12/07)
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- Enantioselective total synthesis of (S)-(-)-quinolactacin B
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The enantioselective total synthesis of (-)-quinolactacin B (-)-1 was performed in seven steps and 33% overall yield from tryptamine. The synthesis features the use of ruthenium catalytic asymmetric hydrogen reaction to introduce the chirality in dihydro-
- Shankaraiah, Nagula,da Silva, Wender A.,Andrade, Carlos Kleber Z.,Santos, Leonardo Silva
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p. 4289 - 4291
(2008/09/21)
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- PROLINAMIDE DERIVATIVES AS SODIUM CHANNEL MODULATORS
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The invention provides a compound of formula (I), a solvate, a salt or prodrug thereof, useful in the treatment of diseases and conditions mediated by modulation of use-dependent voltage-gated sodium channels.
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Page/Page column 27-28
(2008/06/13)
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- QUATERNARY ALPHA-AMINOCARBOXAMIDE DERIVATIVE AS MODULATORS OF VOLTAGE-GATED SODIUM CHANNELS
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The invention relates to quaternary E-aminocarboxyamide derivatives of formula (I), wherein R1, R2, R3, R4, R5, R6, X, q and n are as defined in claim 1, for treating diseases and conditions mediated by modulation of voltage-gated sodium channels.
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Page/Page column 62
(2010/11/27)
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- Malate salts, and polymorphs of (3S,5S)-7-[3-amino-5-methyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid
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The present invention is directed to malate salts of (3S,5S)-7-[3-amino-5-methyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid, and its polymorphs. The present invention is also directed to pharmaceutical compositions comprising the described salts and polymorphs.
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Page/Page column 4-5
(2008/06/13)
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- Coupling process for preparing quinolone intermediates
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Process for making 7-cycloamino-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acids. Borate ester compounds suitable for use in such process.
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Page/Page column 4
(2008/06/13)
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- Acetylenic piperazines as metabotropic glutamate receptor antagonists
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The invention relates to compounds of formula I or pharmaceutically acceptable salts or solvates thereof: where Ar1, A, B, R1, m and n are as defined in the description. The invention also includes pharmaceutical compositions and uses of, and processes of making the compounds, as well as methods of medical treatment of mGluR 5 mediated disorders.
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Page/Page column 27
(2010/11/25)
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- Hydride reduction process for preparing quinolone intermediates
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Hydride process for making acyclic diol intermediates from cyclic intermediates, useful in antibacterial quinolone synthesis.
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Page/Page column 3
(2008/06/13)
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- Two separate and distinct syntheses of stereospecifically deuteriated samples of (2S)-proline
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Two distinct syntheses of samples of the amino acid l-proline which are stereospecifically deuteriated on the β-carbon atom are reported. In the first of these, the labelled diazoketones 6, prepared by a chemico-enzymatic synthesis, have been photolysed in alkaline conditions to give the corresponding labelled methyl pyroglutamates 10 via hydrolysis and intramolecular trapping of the resultant ketene intermediates 9. These were then converted into (2S,3S)-[3-2H1]- and (2S,3R)-[2,3-2H 2]-proline, 1a and 1b respectively. The second synthesis provides (2S)-[3,3-2H2]-, (2S,3S)- and (2S,3R)-[3- 2H1]-proline, 1d, 1a and 1c respectively, and has as its key step the highly stereoselective hydrolysis of the silylenol ethers 14 and 14a respectively in which deuteriation or protonation occurs from the re-face of the enol ether. The Royal Society of Chemistry 2006.
- Barraclough, Paul,Dieterich, Petra,Spray, Caroline A.,Young, Douglas W.
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p. 1483 - 1491
(2008/02/03)
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- AMINOPIPERIDINE QUINOLINES AND THEIR AZAISOSTERIC ANALOGUES WITH ANTIBACTERIAL ACTIVITY
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The present invention relates to compounds that demonstrate antibacterial activity, processes for their preparation, pharmaceutical compositions containing them as the active ingredient, to their use as medicaments and to their use in the manufacture of medicaments for use in the treatment of bacterial infections in warm blooded animals such as humans. In particular this invention relates to compounds useful for the treatment of bacterial infections in warm-blooded animals such as humans, more particularly to the use of these compounds in the manufacture of medicaments for use in the treatment of bacterial infections in warm blooded animals such as humans.
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Page/Page column 58
(2008/06/13)
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- Monatin, its stereoisomers and derivatives: Modeling the sweet taste chemoreception mechanism
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The sweet natural compound monatin 1 has two stereogenic centers, and the 2S,4S absolute configuration has been attributed previously to the natural isomer. Among the four stereoisomers of monatin, three of them, particularly the 2R,4R isomer, tastes intensely sweet. The conformations of the four compounds have been studied by means of molecular modelling techniques. Both the diastereoisomeric forms show strong intramolecular hydrogen bonds which involve different functional groups and give rise to two different minimum energy conformations. The tertiary alcohol group in monatin seems to be indirectly involved in the generation of the taste, acting as an important contraint in generating the active conformation. The most important glucophores have been identified in the terminal -NH3+ and -COO - groups and in the indole ring by comparison with known topological models of sweet compounds and through the synthesis of appropriate derivatives in which some of these groups are lacking or modified. The relative affinity of each stereoisomer for its putative sweet taste receptor has been estimated semi-quantitatively with the pseudoreceptor modelling technique. The predicted activity calculated with this technique is in good agreement with the experimental data and explains why the 2R,4R isomer (and not the natural 2S,4S isomer) is the sweetest of the series. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.
- Bassoli, Angela,Borgonovo, Gigliola,Busnelli, Gilberto,Morini, Gabriella,Merlini, Lucio
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p. 2518 - 2525
(2007/10/03)
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- Novel interleukin-1beta converting enzyme inhibitors
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The present invention relates to interleukin-1β converting enzyme inhibitors having the formula: R is a carbocyclic or heterocyclic ring; R1 is a cysteine trap; R2a, R2a′, R2b, and R2b are each independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy, and mixtures thereof; or R2a′ and R2b′ can taken together to form a double bond; L and L1 are linking groups having the formula: T is selected from the group consisting of: i) —NR6—; ii) —O—; iii) —NR6S(O)2—; iv) —S(O)2NR6—; and v) mixtures thereof; R6 is hydrogen, substituted or unsubstituted C1-C20 linear, branched, or cyclic alkyl, C6-C20 aryl, C7-C20 alkylenearyl, and mixtures thereof; the indices w, w1, and w2 are each independently 0 or 1; i) hydrogen; ii) C1-C4 linear, branched, and cyclic alkyl; iii) R3a and R3b or R4a, and R4b can be taken together to form a carbonyl unit; iv) two R3a or two R3b units from adjacent carbon atoms or two R4a or two R4b units from adjacent carbon atoms can be taken together to form a double bond; and v) mixtures thereof; the index m is from 0 to 5; the index n is from 0 to 5.
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- A concise synthesis of (2S,4R)- and (2S,4S)-4-methylglutamic acid
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A concise, multi-gram scale method for producing the bioactive and enantiomerically pure epimers, (2S,4R)- and (2S,4S)-glutamic acids, in a single synthetic scheme is described.
- Gu, Zi-Qiang,Li, Min
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p. 3203 - 3205
(2007/10/03)
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- A process for the preparation of 3-Glutamido bile ester derivatives using N-tBoc methyl pyroglutamate
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The present invention relates to a novel process for the preparation of bile esters derivatives of general formula (I), in which R1 is H or OH; R2 is H, α-OH or β-OH and R3 is a straight or branched C1-C4 alkyl group or a benzyl group.The process uses either L-glutamic acid hydrochloride (II) or L-glutamic acid as starting material, according to the following Scheme 1.
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