- Synthesis ofN-Boc-α-amino Acids from Carbon Dioxide by Electrochemical Carboxylation ofN-Boc-α-aminosulfones
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Electrochemical reduction ofN-Boc-α-aminosulfones in DMF using an undivided cell equipped with a Pt plate cathode and an Mg rod anode under atmospheric pressure of bubbling carbon dioxide through the solution under constant current conditions resulted in a reductive C-S bond cleavage with elimination of benzenesulfinate ion generating the corresponding anion species followed by fixation of carbon dioxide to give the correspondingN-Boc-α-amino acids in moderate to good yields.
- Senboku, Hisanori,Minemura, Yoshihito,Suzuki, Yuto,Matsuno, Hidetoshi,Takakuwa, Mayu
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p. 16077 - 16083
(2021/10/12)
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- Discovery of M3Antagonist-PDE4 Inhibitor Dual Pharmacology Molecules for the Treatment of Chronic Obstructive Pulmonary Disease
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In this paper, we report the discovery of dual M3 antagonist-PDE4 inhibitor (MAPI) compounds for the inhaled treatment of pulmonary diseases. The identification of dual compounds was enabled by the intuition that the fusion of a PDE4 scaffold derived from our CHF-6001 series with a muscarinic scaffold through a common linking ring could generate compounds active versus both the transmembrane M3 receptor and the intracellular PDE4 enzyme. Two chemical series characterized by two different muscarinic scaffolds were investigated. SAR optimization was aimed at obtaining M3 nanomolar affinity coupled with nanomolar PDE4 inhibition, which translated into anti-bronchospastic efficacy ex vivo (inhibition of rat trachea contraction) and into anti-inflammatory efficacy in vitro (inhibition of TNFα release). Among the best compounds, compound 92a achieved the goal of demonstrating in vivo efficacy and duration of action in both the bronchoconstriction and inflammation assays in rat after intratracheal administration.
- Armani, Elisabetta,Rizzi, Andrea,Capaldi, Carmelida,De Fanti, Renato,Delcanale, Maurizio,Villetti, Gino,Marchini, Gessica,Pisano, Anna Rita,Pitozzi, Vanessa,Pittelli, Maria Gloria,Trevisani, Marcello,Salvadori, Michela,Cenacchi, Valentina,Puccini, Paola,Amadei, Francesco,Pappani, Alice,Civelli, Maurizio,Patacchini, Riccardo,Baker-Glenn, Charles A.G.,Van De Po?l, Hervé,Blackaby, Wesley P.,Nash, Kevin,Amari, Gabriele
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supporting information
p. 9100 - 9119
(2021/07/19)
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- ALLOSTERIC EGFR INHIBITORS AND METHODS OF USE THEREOF
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The disclosure relates to compounds that act as an allosteric inhibitors of epidermal growth factor receptor (EGFR); pharmaceutical compositions comprising the compounds; and methods of treating or preventing kinase-mediated disorders, including cancer and other proliferation diseases.
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Page/Page column 62-63; 90
(2021/01/22)
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- Mechanism of Oxidative Amidation of Nitroalkanes with Oxygen and Amine Nucleophiles by Using Electrophilic Iodine
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Recently, we developed a direct method to oxidatively convert primary nitroalkanes into amides that entailed mixing an iodonium source with an amine, base, and oxygen. Herein, we systematically investigated the mechanism and likely intermediates of such methods. We conclude that an amine-iodonium complex first forms through N-halogen bonding. This complex reacts with aci-nitronates to give both α-iodo- and α,α-diiodonitroalkanes, which can act as alternative sources of electrophilic iodine and also generate an extra equimolar amount of I+ under O2. In particular, evidence supports α,α-diiodonitroalkane intermediates reacting with molecular oxygen to form a peroxy adduct; alternatively, these tetrahedral intermediates rearrange anaerobically to form a cleavable nitrite ester. In either case, activated esters are proposed to form that eventually reacts with nucleophilic amines in a traditional fashion.
- Li, Jing,Lear, Martin J.,Kwon, Eunsang,Hayashi, Yujiro
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p. 5538 - 5542
(2016/04/20)
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- Oxidative Amidation of Nitroalkanes with Amine Nucleophiles using Molecular Oxygen and Iodine
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The formation of amides and peptides often necessitates powerful yet mild reagent systems. The reagents used, however, are often expensive and highly elaborate. New atom-economical and practical methods that achieve such goals are highly desirable. Ideally, the methods should start with substrates that are readily available in both chiral and non-chiral forms and utilize cheap reagents that are compatible with a wide variety of functional groups, steric encumberance, and epimerizable stereocenters. A direct oxidative method was developed to form amide and peptide bonds between amines and primary nitroalkanes simply by using I2 and K2CO3 under O2. Contrary to expectations, a 1:1 halogen-bonded complex forms between the iodonium source and the amine, which reacts with nitronates to form α-iodo nitroalkanes as precursors to the amides.
- Li, Jing,Lear, Martin J.,Kawamoto, Yuya,Umemiya, Shigenobu,Wong, Alice R.,Kwon, Eunsang,Sato, Itaru,Hayashi, Yujiro
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p. 12986 - 12990
(2015/11/02)
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- HETEROARYL DERIVATIVES
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Compounds of formula (I) described herein are both phosphodiesterase 4 (PDE4) enzyme inhibitors and muscarinic M3 receptor antagonists and are useful for the prevention and/or treatment of diseases of the respiratory tract characterized by airway obstruction.
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Paragraph 0502; 0503; 0504
(2015/06/17)
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- HETEROARYL DERIVATIVES FOR THE TREATMENT OF RESPIRATORY DISEASES
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The invention relates to novel compounds of formula (I) which are both phosphodiesterase 4 (PDE4) enzyme inhibitors and muscarinic M3 receptor antagonists, methods of preparing such compounds, compositions containing them and therapeutic use thereof.
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Page/Page column 116; 117
(2015/06/18)
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- Dual Catalytic Decarboxylative Allylations of α-Amino Acids and Their Divergent Mechanisms
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The room temperature radical decarboxylative allylation of N-protected α-amino acids and esters has been accomplished via a combination of palladium and photoredox catalysis to provide homoallylic amines. Mechanistic investigations revealed that the stability of the α-amino radical, which is formed by decarboxylation, dictates the predominant reaction pathway between competing mechanisms.
- Lang, Simon B.,O'Nele, Kathryn M.,Douglas, Justin T.,Tunge, Jon A.
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supporting information
p. 18589 - 18593
(2016/01/25)
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- ANTI-PCSK9 COMPOUNDS AND METHODS FOR THE TREATMENT AND/OR PREVENTION OF CARDIOVASCULAR DISEASES
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Disclosed are compounds that modulate the physiological action of the proprotein convertase subtilisin kexin type 9 (PCSK9), and methods of using these modulators to reduce LDL-cholesterol levels and/or for the treatment and/or prevention of cardiovascular disease (CVD), including treatment of hypercholesterolemia.
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Page/Page column 32
(2014/10/04)
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- One-step synthesis of racemic α-amino acids from aldehydes, amine components, and gaseous CO2 by the aid of a bismetal reagent
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α-Amino acids are essential resources for human life and are highly useful as building blocks for organic synthesis. The core framework of an α-amino acid can be divided into three basic components: an aldehyde, an amine, and carbon dioxide (CO2). We report herein that a one-step synthesis of α-amino acids has been successfully achieved from these three basic and inexpensive chemicals with a single operation, in which the mixture of an aldehyde, a sulfonamide, and gaseous CO2 was heated at 100 °C in the presence of Bu3Sn-SnBu3 and CsF. In this one-pot sequential protocol, two important intermediates (imine and α-amino stannane) are involved and the stannyl anion generated in situ plays a crucial role, particularly for the efficient stannylation of the imine in the presence of proton sources and for promoting retrostannylation of the undesired α-alkoxy stannane owing to its high stability and tolerance of the presence of proton sources. This methodology enabled the synthesis of a wide range of racemic arylglycine derivatives in high yields. Go retro! α-Amino acids are essential resources for human life and are highly useful as building blocks for organic synthesis. The core framework of an α-amino acid is retrosynthesized to an aldehyde, an amine, and carbon dioxide. A one-step synthesis of α-amin Copyright
- Mita, Tsuyoshi,Higuchi, Yuki,Sato, Yoshihiro
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p. 1123 - 1128
(2013/02/23)
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- Synthesis of arylglycine and mandelic acid derivatives through carboxylations of α-amido and α-acetoxy stannanes with carbon dioxide
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Incorporation reactions of carbon dioxide (CO2) with N-Boc-α-amido and α-acetoxy stannanes were developed using CsF as a mild tin activator. Monoprotected α-amido stannanes could be used, and the corresponding arylglycine derivatives were obtained in moderate-to-high yields under 1 MPa (10 atm) of CO2 pressure. α-Acetoxy stannanes also underwent carboxylation to afford mandelic acid derivatives in excellent yields under ambient CO2 pressure. Both transformations enabled the synthesis of α-tertiary and α-quaternary carboxylic acid derivatives. In addition, the chirality of (S)-N-tert-butylsulfonyl-α- amido stannanes was transferred with up to 90% inversion of configuration at 100 °C.
- Mita, Tsuyoshi,Sugawara, Masumi,Hasegawa, Hiroyuki,Sato, Yoshihiro
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experimental part
p. 2159 - 2168
(2012/06/01)
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- One-pot synthesis of α-amino acids from CO2 using a bismetal reagent with Si-B bond
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In the presence of 1.1 equiv of PhMe2Si-Bpin, 5 equiv of CsF, and 20 mol % of TsOH·H2O, precursors of N-Boc-imines can be converted into the corresponding α-aryl or α-alkenyl glycine derivatives under gaseous CO2 in moderate-to-high yields with a single operation. α-Isobutenyl glycine thus obtained can be further derivatized into various types of α-amino acids including N-Boc-leucine, serine, and glycine derivatives in short steps.
- Mita, Tsuyoshi,Chen, Jianyang,Sugawara, Masumi,Sato, Yoshihiro
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supporting information
p. 6202 - 6205
(2013/02/23)
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- GLYCINE DERIVATIVES AND THEIR USE AS MUSCARINIC RECEPTOR ANTAGONISTS
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The present invention relates to alkaloid aminoester derivatives acting as muscarinic receptor antagonists, processes for their preparation, compositions comprising them and therapeutic uses thereof.
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Page/Page column 31
(2012/06/15)
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- GLYCINE DERIVATIVES AND MEDICINAL COMPOSITIONS THEREOF
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Alkaloid aminoester derivatives according to formula (I) and (VI) act as muscarinic receptor antagonists.
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Page/Page column 11
(2012/06/16)
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- One-pot synthesis of α-amino acids from imines through CO2 incorporation: An alternative method for strecker synthesis
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Itas a gas: A novel one-pot process for the synthesis of α-amino acids from imine equivalents using CO2 gas as a carbon source has been developed. This reaction was made possible by the reagent combination of TMSSnBu3 and CsF (see scheme). Three successive reactions (imine formation, stannylation, and carboxylation) proceeded in the same flask under these conditions to give products in up to 79 % yield. Boc=tert-butoxycarbonyl, TMS=trimethylsilyl.
- Mita, Tsuyoshi,Chen, Jianyang,Sugawara, Masumi,Sato, Yoshihiro
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p. 1393 - 1396
(2011/04/22)
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- Discovery of small molecules that enhance astrocyte differentiation in rat fetal neural stem cells
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1,3,4-Oxadiazole derivatives were found to enhance astrocyte differentiation in rat fetal neural stem cells (NSCs). Differentiation activity was assessed by immunocytochemistry and analysis of mRNA expression of astrocyte markers, GFAP and S100. Compounds 7 and 8 showed approximately a two-fold increase in astrocyte differentiation without engagement of neuronal differentiation and detectable cytotoxicity.
- Chang, Dong Jo,Jeong, Mi Young,Song, Jiho,Jin, Chang Yun,Suh, Young-Ger,Kim, Hyun-Jung,Min, Kyung Hoon
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supporting information; scheme or table
p. 7050 - 7053
(2012/01/13)
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- Enantiomeric resolution of α-amino acid derivatives on two diastereomeric chiral stationary phases based on chiral crown ethers incorporating two different chiral units
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Two diastereomeric chiral stationary phases (CSPs) were applied to the liquid chromatographic resolution of various racemic a-amino methyl esters, α-amino N,N-diethylamides and α-amino N-propylamides. The CSP incorporating (R)-3,3' -diphenyl-1,1' -binaphtyl and (R,R)-tartaric acid unit as chiral barriers did not show any chiral recognition. In contrast, the CSP incorporating (R)-3,3'-diphenyl-1,1'-binaphtyl and (S,S)-tartaric acid unit as chiral barriers was found to show excellent chiral recognition especially for the two enantiomers of a-amino N-propylamides. Some of a-amino methyl esters and α-amino N,N-diethylamides were also resolved on the CSP incorporating (R)-3,3'-diphenyl-1,1'-binaphtyl and (S,S)-tartaric acid unit. From these results it was concluded that the two chiral units composing the diastereomeric CSPs can show "matched" or "mismatched" effect on the chiral recognition according to their absolute stereochemistry.
- Kim, Hee Jin,Choi, Hee Jung,Cho, Yoon Jae,Hyun, Myung Ho
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body text
p. 1551 - 1554
(2010/10/20)
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- COMPOUNDS HAVING ACTIVITY IN INCREASING ION TRANSPORT BY MUTANT-CFTR AND USES THEREOF
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The invention provides compositions, pharmaceutical preparations and methods for increasing activity of a mutant cystic fibrosis transmembrane conductance regulator protein (mutant-CFTR). The compositions pharmaceutical preparations and methods are useful for the study and treatment of disorders associated with mutant-CFTR, such as cystic fibrosis. The compositions and pharmaceutical preparations of the invention may comprise one or more phenylglycine-containing compounds of the invention, or an analog or derivative thereof
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Page/Page column 53
(2009/05/28)
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- 1,8-Naphthyridine-3-carboxamide derivatives with anticancer and anti-inflammatory activity
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A number of 1-propargyl-1,8-naphthyridine-3-carboxamide derivatives (15-35) have been synthesized and screened for their in vitro cytotoxicity and anti-inflammatory activity. Compounds 22, 31 and 34 have shown high cytotoxicity against a number of cancer cell lines, while compound 24 showed significant anti-inflammatory activity.
- Kumar, Vivek,Jaggi, Manu,Singh, Anu T.,Madaan, Alka,Sanna, Vinod,Singh, Pratibha,Sharma, Pramod K.,Irchhaiya, Raghuveer,Burman, Anand C.
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experimental part
p. 3356 - 3362
(2009/10/23)
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- Novel thiazolones as HCV NS5B polymerase allosteric inhibitors: Further designs, SAR, and X-ray complex structure
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Structure-activity relationships (SAR) of 1 against HCV NS5B polymerase were described. SAR explorations and further structure-based design led to the identifications of 2 and 3 as novel HCV NS5B inhibitors. X-ray structure of 3 in complex with NS5B polymerase was obtained at a resolution of 2.2 A, and confirmed the design.
- Yan, Shunqi,Larson, Gary,Wu, Jim Z.,Appleby, Todd,Ding, Yili,Hamatake, Robert,Hong, Zhi,Yao, Nanhua
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- METHOD FOR PRODUCING SOLUTION CONTAINING N-t-BUTYLOXYCARBONYLAMINO ACID
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PROBLEM TO BE SOLVED: To provide a method for producing a solution containing an N-t-butyloxycarbonylamino acid (BOCA) with which the production efficiency is good. SOLUTION: The method for producing the solution containing the BOCA comprises the following steps (a) to (c). (a) A step of reacting di-t-butyl dicarbonate with an amino acid in an amount of equivalent based on the carbonate in the presence of an organic solvent immiscible with water, a base and water and affording a reaction mixture containing a salt of the BOCA, (b) a step of adding an acid to the reaction mixture, producing the free BOCA and extracting the produced BOCA with the organic solvent immiscible with water and (c) a step of separating an organic phase containing the BOCA obtained in the step (b) and the organic solvent immiscible with water from an aqueous phase containing a salt produced by a neutralizing reaction of the acid with the base.
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Page/Page column 8
(2008/06/13)
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- Chiral gelators constructed from 11-aminoundecanoic (AUDA), lauric and amino acid units. Synthesis, gelling properties and preferred gelation of racemates vs. the pure enantiomers
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A new class of efficient low molecular weight gelator molecules has been designed by combining 11-aminoundecanoic acid (AUDA), lauric acid and aromatic and aliphatic amino acid units in the same molecule. This yields a special class of fatty acid amphiphiles with core chiral centres and hydrogen bonding sites. Some of the compounds with terminal carboxylic acid and sodium carboxylate functions exhibited ambidextrous gelation properties, being able to form gels both with highly polar solvents (water, DMSO) and also with highly lipophilic solvents, including two hydrocarbon fuels. At variance with several recent observations that the enantiomers are generally more efficient gelators than the corresponding racemates, some of the racemic gelators prepared in this work were found to be capable of gelling up to 16 times larger volumes of certain solvents than the pure enantiomers. Temperature-dependent FTIR and 1H NMR studies of the gels formed by derivatives with terminal carboxylic acid groups and lipophilic solvents revealed that intermolecular hydrogen bonding between amidic and carboxylic acid units was involved in the self-assembly of gel aggregates. Additional strong stabilization of the aggregates was observed in the gelators possessing terminal sodium carboxylate groups, and this was attributed to the electrostatic and ion-dipole interactions between the sodium carboxylate groups. This additional stabilization appears to be responsible for considerably higher thermal stability of the latter gels in relation to those formed by gelators with terminal carboxylic acid groups. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
- Caplar, Vesna,Zinic, Mladen,Pozzo, Jean-Luc,Fages, Frederic,Mieden-Gundert, Gudrun,Voegtle, Fritz
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p. 4048 - 4059
(2007/10/03)
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- ARYLGLYCINE DERIVATIVES AND THEIR USE AS GLYCINE TRANSPORT INHIBITORS
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The present invention relates to compounds of Formula (I), and salts solvates and hydrates thereof. The invention further relates to pharmaceutical compositions containing said compounds and methods of treating neurological, neuropsychiatric, and gastrointestinal disorders using said compounds.
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- ARYLGLYCINE DERIVATIVES FOR USE AS GLYCINE TRANSPORT INHIBITORS
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The present invention relates to compounds of Formula (I) and salts solvates and hydrates thereof. The invention further relates to pharmaceutical compositions containing said compounds and methods of treating neurological and neuropsychistric disorders using said compounds.
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- Heterocyclic compounds as inhibitors of rotomase enzymes
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Compounds of the formula: wherein R1, Y, W, A and R2are as defined above are inhibitors of rotamase enzymes in particular FKBP-12 and FKBP-52. The compounds therefore moderate neuronal regeneration and outgrowth and can be used for treating neurological disorders arising from neurodegenerative diseases and nerve damage.
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- Antithrombotic azacycloalkylalkanoyl peptides and pseudopeptides
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The present invention relates to azacycloalkylalkanoyl peptides and pseudopeptides which inhibit platelet aggregation and thrombus formation thereby being useful in the prevention and treatment of thrombosis associated with disease states such as myocardial infarction, stroke, peripheral arterial disease, and disseminated intravascular coagulation, to methods for the prevention or treatment of thrombosis in a mammal in need of such therapy comprising the administration of a therapeutically effective amount of such compounds, and to pharmaceutical compositions comprising such compounds.
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- New facile alkoxycarbonylating agent, alkyl pyrazole-1-carboxylates. The preparation and the utilities
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Alkyl pyrazole-1-carboxylates (2), which were readily prepared from alkyl chloroformate or carbazate in good yields, were provided as the new facile alkoxycarbonylating agents toward the Grignard reagents for the synthesis of one carbon higher carboxylic esters. Also amines were alkoxycarbonylated by 2 to produce the corresponding urethanes even in an aqueous medium. Benzyl 3,5-dimethylpyrazole-1-carboxylate (2d) could be utilized for the Cbz-protection of amino acids and esters in good yield without any racemization.
- Kashima, Choji,Tsuruoka, Shiro,Mizuhara, Saori
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p. 14679 - 14688
(2007/10/03)
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- Site selective substitution of carbamate and carbamoyl protected benzylamines
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Methoxy and fluoro substituted benzylamines can be metalated optionally at the position adjacent to the nitrogen bearing side chain or adjacent to the hetero substituent as a function of the acyl type protective group.
- Katsoulos,Schlosser
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p. 6263 - 6264
(2007/10/02)
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- A STEREOSELECTIVE SYNTHESIS OF N-BOC-α-AMINO ALCOHOLS AND α-AMINO ACIDS
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A sterteoselective synthesis of N-Boc-α-amino alcohols and α-amino acids via the addition of Grignard reagents to the chiral electrophilic glycine equivalent α-bromo-N-Boc-glycine(-)phenylmenthylester is described.
- Ermert, Philipp,Meyer, Jsabella,Stucki, Christoph,Schneebeli, Joerg,Obrecht, Jean-Pierre
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p. 1265 - 1268
(2007/10/02)
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