- Stable cyclopropene-containing analogs of the amino acid neurotransmitter glutamate
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As a neurotransmitter, the amino acid glutamate has been the subject of efforts to generate structural analogs with unique properties. Here we report a practical, half-gram synthesis of two cyclopropene-containing glutamate analogs. These analogs are stable in solution, in the presence of the biological nucleophile glutathione, upon concentration, and during long-term storage, while maintaining their amenability to photo- or enzyme-caging and reactivity with bioorthogonal reaction partners like s-tetrazine or light-activated tetrazoles.
- Kumar, Pratik,Huang, Wei,Shukhman, David,Camarda, Frank M.,Laughlin, Scott T.
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p. 1476 - 1480
(2019/05/07)
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- 6-SUBSTITUTED 3-FLUORO-2-PYRIDINALDOXIME, 3-FLUORO-2-PYRIDINE HYDROXAMIC ACID, AND 3-FLUORO-2-PYRIDINAMIDOXIME SCAFFOLDS
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The present invention relates to a compound of formula (I), as well as to a process for preparing the compounds of formula (I) by a chemoselective Sonogashira reaction. It also relates to a pharmaceutical composition comprising at least one compound of formula (I) and at least one pharmaceutically acceptable support. Finally, it relates to the use of such a compound as a medicine, preferably in the treatment of a nervous and/or respiratory failure due to intoxication with at least one organophosphorous nerve agent; in the treatment of neurological diseases such as Alzheimer's disease; and/or in the treatment of cancer; and/or for use as antiviral drug.
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Paragraph 0045; 0109; 0110
(2019/05/04)
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- Design, synthesis and biological evaluation of C(4) substituted monobactams as antibacterial agents against multidrug-resistant Gram-negative bacteria
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A series of novel pyridone conjugated monobactams with various substituents at the (4) position were synthesized and evaluated for their antibacterial activities against a panel of multidrug-resistant (MDR) Gram-negative bacteria in vitro. Compounds 46d, 54 and 75e displayed good to moderate activities against P. aeruginosa, among which the activity of 75e against P. aeruginosa was comparable to that of BAL30072 under iron limitation condition. Compounds 35, 46d, 54, 56a, 56c and 56d exhibited good to excellent antibacterial activities against E. coli and K. pneumoniae, which were comparable or superior to that of BAL30072. In vitro liver microsomal stability was further evaluated and the results manifested that Compounds 35, 46d and 54 were metabolically stable in human liver microsomes.
- Kou, Qunhuan,Wang, Ting,Zou, Feng,Zhang, Shuhua,Chen, Qian,Yang, Yushe
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- Sonogashira Reaction of Bromofluoropyridinaldoxime Nuclei: Convergent Synthesis of Functionalized 2- and 3-Fluoropyridine Scaffolds
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A chemoselective palladium catalyzed Sonogashira cross-coupling of bromofluoropyridinaldoxime with highly functionalized alkynes is presented. This reaction is fully compatible with unprotected sensitive aldoxime and affords representative underexplored new scaffolds. The process exhibits a broad scope of alkynes, dialkynes, and large functional group compatibility, including the use of non-radioactive isotopic reporter such as 15N labeled oxime and chiral substrates.
- Yerri, Jagadeesh,Baati, Rachid
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supporting information
p. 4161 - 4165
(2018/08/21)
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- Ligand-Enabled Alkynylation of C(sp3)?H Bonds with Palladium(II) Catalysts
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The palladium(II)-catalyzed β- and γ-alkynylation of amide C(sp3)?H bonds is enabled by pyridine-based ligands. This alkynylation reaction is compatible with substrates containing α-tertiary or α-quaternary carbon centers. The β-methylene C(sp
- Fu, Haiyan,Shen, Peng-Xiang,He, Jian,Zhang, Fanglin,Li, Suhua,Wang, Peng,Liu, Tao,Yu, Jin-Quan
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p. 1873 - 1876
(2017/02/05)
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- Gold-Catalyzed Cycloisomerization of Alkyne-Containing Amino Acids: Controlled Tuning of C–N vs. C–O Reactivity
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Versatile alkyne-containing amino acids were used as ambident precursors in the divergent synthesis of alkylidenelactones and 1-pyrrolines. Two gold-catalyzed protocols were applied for selective intramolecular O- and N-cycloisomerization reactions.
- Medran, Noelia S.,Villalba, Matías,Mata, Ernesto G.,Testero, Sebastián A.
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p. 3757 - 3764
(2016/08/16)
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- α-Propargyl amino acid-derived optically active novel substituted polyacetylenes: Synthesis, secondary structures, and responsiveness to ions
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Novel optically active substituted acetylenes HCi£ CCH 2CR1(CO2CH3)NHR2 [(S)-/(R)-1: R1 = H, R2 = Boc, (S)-2: R1 = CH3, R2 = Boc, (S)-3: R1 = H, R2 = Fmoc, (S)-4: R1 = CH3, R2 = Fmoc (Boc = tert-butoxycarbonyl, Fmoc = 9-fluorenylmethoxycarbonyl)] were synthesized from α-propargylglycine and α-propargylalanine, and polymerized with a rhodium catalyst to provide the polymers with number-average molecular weights of 2400-38,900 in good yields. Polarimetric, circular dichroism (CD), and UV-vis spectroscopic analyses indicated that poly[(S)-1], poly[(R)-1], and poly[(S)-4] formed predominantly one-handed helical structures both in polar and nonpolar solvents. Poly[(S)-1a] carrying unprotected carboxy groups was obtained by alkaline hydrolysis of poly[(S)-1], and poly[(S)-4b] carrying unprotected amino groups was obtained by removal of Fmoc groups of poly[(S)-4] using piperidine. Poly[(S)-1a] and poly[(S)-4b] also exhibited clear CD signals, which were different from those of the precursors, poly[(S)-1] and poly[(S)-4]. The solution-state IR measurement revealed the presence of intramolecular hydrogen bonding between the carbamate groups of poly[(S)-1] and poly[(S)-1a]. The plus CD signal of poly[(S)-1a] turned into minus one on addition of alkali hydroxides and tetrabutylammonium fluoride, accompanying the red-shift of λmax. The degree of λmax shift became large as the size of cation of the additive.
- Sogawa, Hiromitsu,Shiotsuki, Masashi,Sanda, Fumio
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p. 2008 - 2018
(2012/07/13)
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- BROAD SPECTRUM ANTIBIOTICS
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Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. The compounds provided herein can in other embodiments overcome the resistance conferred by single amino acid mutations at defined posi
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Page/Page column 194
(2013/02/27)
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- Synthesis of optically active α-(allenyl)-and a-substituted-α- (allenyl)glycines
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The synthesis of various types of optically active α-(allenylsilane- containing)glycines via a chiralitytransferring ester-enolate Claisen rearrangement of α-acyloxy-a-alkynylsilanes is described. The conversion of the rearranged products into the optically active silicon-free α-(allenyl)-and α-substituted-α-(allenyl)glycines was achieved by the removal of the Me2PhSi-or TMS group from the allene terminus.
- Takuya Okada,Oda, Naoko,Suzuki, Hiroyuki,Sakaguchi, Kazuhiko,Ohfune, Yasufumi
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supporting information; experimental part
p. 3765 - 3768
(2010/08/22)
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- 1,2,3-Triazolyl amino acids as AMPA receptor ligands
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The central nervous system glutamate receptors are an important target for drug discovery. Herein we report initial investigations into the synthesis and glutamate receptor activity of 1,2,3-triazolyl amino acids. Two compounds were found to be selective
- Stanley,Pedersen, D. Sejer,Nielsen,Kvist,Mathiesen,Br?uner-Osborne,Taylor,Abell
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p. 7512 - 7515
(2011/03/17)
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- AMINO ACID INHIBITORS OF CYTOCHROME P450
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Methods of inhibiting cytochrome P450 enzymes are provided that can be used for improving the treatment of diseases by preventing degradation of drugs or other molecules by cytochrome P450. Pharmaceutical compositions are provided that can act as boosters
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Page/Page column 73-74
(2009/10/18)
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- 5-[5-[2-(3,5-BIS(TRIFLUOROMETHYL)PHENYL)-2-METHYLPROPANOYLMETHYLAMINO]-4-(4-FLUORO-2-METHYLPHENYL)]-2-PYRIDINYL-2-ALKYL-PROLINAMIDE AS NK1 RECEPTOR ANTAGONISTS
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The invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is C1-4 alkyl useful in the treatment of diseases and conditions for which antagonism of NK1 receptor is beneficial.
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- Novel Compounds
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The invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is C1-4 alkyl useful in the treatment of diseases and conditions for which antagonism of NK1 receptor is beneficial.
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Page/Page column 20
(2009/12/05)
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- Practical syntheses of chiral α-amino acids and chiral half-esters by kinetic resolution of urethane-protected α-amino acid N-carboxyanhydrides and desymmetrization of cyclic meso-anhydrides with new modified cinchona alkaloid catalysts
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The large-scale applications of the kinetic resolution of urethane-protected α-amino acid N-carboxyanhydrides (UNCAs) and the desymmetrization of cyclic meso-anhydrides using modified cinchona alkaloids are described. These asymmetric reactions are effective organocatalytic methods for the synthesis of chiral a-amino acids 6 and chiral half-esters 2 on an industrial scale, because the organocatalyst recovery and product purification can be carried out by a simple extractive procedure obviating a chromatographic purification step. The modified cinchona alkaloid catalysts (DHQD) 2AQN and (DHQ)2AQN, as reported by Deng and co-workers, are not readily available and therefore not suitable for industrial-scale synthesis. Various O-alkylated quinidine and quinine derivatives were prepared and screened as catalysts for the kinetic resolution of phenylalanine UNCA with alcohol. The readily prepared O-propargylquinidine (OPQD) and O-propargylquinine (OPQ) were discovered to be highly enantioselective and practical catalysts. These new catalysts were applied to the synthesis of chiral propargylglycine 24 and the key intermediate of BAY10-8888/PLD-118, 26, on an industrial scale, by the kinetic resolution of UNCA 22 and the desymmetrization of cyclic meso-anhydride 25, respectively.
- Ishii, Yutaka,Fujimoto, Ryosuke,Mikami, Masafumi,Murakami, Satoshi,Miki, Yasushi,Furukawa, Yoshiro
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p. 609 - 615
(2012/12/31)
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- Cu(I)-catalyzed intramolecular cyclization of alkynoic acids in aqueous media: A "click side reaction"
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(Chemical Equation Presented) Alkynoic acids, in particular, 4-pentynoic acid derivatives, undergo intramolecular cyclizations to enol lactones under reaction conditions typically applied for the Cu(I)-catalyzed cycloaddition of terminal alkynes and azide
- Mindt, Thomas L.,Schibli, Roger
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p. 10247 - 10250
(2008/03/28)
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- MODULATORS OF CELLULAR ADHESION
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The present invention provides compounds having formula (I): and pharmaceutically acceptable derivatives thereof, wherein R1-R4, n, p, A, B, D, E, L and AR1 are as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of disorders mediated by the CD11/CD18 family of cellular adhesion molecules (e.g., LFA-1).
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Page/Page column 82
(2010/02/11)
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- Assembling heterocycle-tethered C-glycosyl and α-amino acid residues via 1,3-dipolar cycloaddition reactions
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(Equation Presented) The 1,3-dipolar cycloadditions of C-glycosyl nitrile oxides and acetylenes to an alkyne and an azide, respectively, bearing a masked glycinyl moiety furnished disubstituted isoxazoles and triazoles. Unveiling the glycinyl group in the
- Dondoni, Alessandro,Giovannini, Pier Paolo,Massi, Alessandro
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p. 2929 - 2932
(2007/10/03)
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- Transition metal-catalyzed synthesis of novel biologically relevant tryptophan analogues
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A synthetic approach to the synthesis of novel tryptophan derivatives and benzofuran-containing amino acids is detailed. The sequence starts from enzymatically resolved enantiopure acetylene-containing amino acids, of which the acetylene function can be e
- Van Esseveldt, Bart C. J.,Van Delft, Floris L.,Smits, Jan M. M.,De Gelder, Rene,Schoemaker, Hans E.,Rutjes, Floris P. J. T.
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p. 823 - 834
(2007/10/03)
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- Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
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There is disclosed a genus of non-peptidyl compounds, wherein said compounds are VLA-4 inhibitors useful in treating inflammatory, autoimmune, and respiratory diseases, and wherein said compounds comprise a compound of Formula (1.0.0): and pharmaceutically acceptable salts and other prodrug derivatives thereof, wherein: A is (C1-C6) alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally substituted with 0 to 3 R9; or is a member selected from the group consisting of the following radicals: A1-NHC(═O)NH-A2-, A1-NHC(═O)O-A2-, A1-OC(═O)NH-A2-, A1-NHSO2NH-A2-, A1-NHC(═O)-A2-, A1-C(═O)NH-A2-, A1-NHSO2-A2-, A1-SO2NH-A2-, A1-(CH2)r-A2-, where A1 and A2 are each independently selected from the group consisting of hydrogen, aryl, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, cycloalkyl, heteroaryl, and heterocyclyl substituted with 0 to 3 R9; B is a member independently selected from the group consisting of the following: E is a single bond; —O—; —NR10—; —CH═CH—; —CC—; —S(═)q; —CR11R12NR10—; or —CR11R12; X is —O—; —C(═O)—; —S(═O)q—; or —NR10—; X1, X2 and X3 are each independently selected from the group consisting of CH, CR9 or N; Y is a single bond; —C(═O)—; —C(═S)—; or —S(═O)2—; R7 is (C1-C6) alkyl; (CH2)kOR5; (CH2)kNR6C(═O)R5; (CH2)kNR6C(═O)OR5; (CH2)kNR6SO2R5; (CH2)kNR6R5; F; CF3; OCF3; aryl, substituted with 0 to 3 R9; heterocyclyl, substituted with 0 to 3 R9; heteroaryl, substituted with 0 to 3 R9; cycloalkyl, substituted with 0 to 3 R9; or R7 may be taken together with R8 to form a cycloalkyl or heterocyclyl ring; or R7 may be taken together with R11 to form a cycloalkyl or heterocyclyl ring; and R8 is hydrogen; F; (C1-C6) alkyl or (C1-C6) alkoxy.
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- Development of new carboxylic acid-based MMP inhibitors derived from functionalized propargylglycines
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A series of carboxylic acids were prepared from a propargylglycine scaffold and tested for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for four enzymes within the MMP family. The inhibitors were typically
- Natchus,Bookland,Laufersweiler,Pikul,Almstead,De,Janusz,Hsieh,Gu,Pokross,Patel,Garver,Peng,Branch,King,Baker,Foltz,Mieling
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p. 1060 - 1071
(2007/10/03)
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- Vinylogous amide analogues of diaminopimelic acid (DAP) as inhibitors of enzymes involved in bacterial lysine biosynthesis.
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[reaction: see text] Vinylogous amides 5 and 6 have been synthesized from L-propargyl glycine and tested against diaminopimelate (DAP) enzymes involved in bacterial lysine biosynthesis. Both are reversible inhibitors of DAP D-dehydrogenase and DAP epimerase with IC(50) values in the 500 microM range. Compound 5 shows competitive inhibition against the L-dihydrodipicolinate (DHDP) reductase with a K(i) value of 32 microM, which is comparable to the planar dipicolinate 16 (K(i) = 26 microM), the best known inhibitor of the enzyme.
- Caplan,Zheng,Blanchard,Vederas
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p. 3857 - 3860
(2007/10/03)
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- Stereoselective, nonracemic synthesis of ω-borono-α-amino acids
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ω-Unsaturated α-amino acids are synthesized through condensation of allyl and propargyl bromides or of 9-bromoundecene with a Ni(II) complex of the Schiff base derived from glycine and BPB. Hydroboration with Ipc2BH followed by oxidation with acetaldehyde affords enantiomerically pure ω- borono-α-aminocarboxylic acids.
- Collet, Sylvain,Bauchat, Patrick,Danion-Bougot, Renee,Danion, Daniel
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p. 2121 - 2131
(2007/10/03)
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- Zinc mediated addition of active halides to a glycine cation equivalent: Synthesis of N-Boc-L-propargylglycine
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The reaction of allylic, benzylic and propargylic halides with zine in the presence of the glycine cation equivalent, methyl N-Boc-2-acetoxyglycine, affords Boc protected amino acid derivatives in high yield. Resolution of methyl N-Boc- propargylglycine w
- Abood, Norman A.,Nosal, Roger
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p. 3669 - 3672
(2007/10/02)
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- The synthesis of [4-carboranylalanine,5-leucine]-enkephalin
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The title compound, an analogue of [Leu5]-enkephalin with L-O-carboranylalanine replacing L-phenylalanine in position 4, was prepared by fragment condensation. The analogue has a 3-fold higher affinity for rat brain opiate receptors in the [3H]naloxone competition assay than natural [Leu5]-enkephalin. Like [Leu5]-enkephalin and Na-acetyl-[Leu5]-enkephalin, the N-terminal tripeptide fragment, H Tyr-Gly-Gly OH, had no melanotropic activity in the Rana pipiens frog skin assay. A convenient, direct synthesis of methyl t-butoxycarbonyl-L-o-carboranylalaninate from methyl t-butoxycarbonyl-L-propargylglycinate is described, and the 13C-NMR, spectra of L-O-carboranylalanine recorded. The procedure was extended to the preparation of BOC Car-Leu OMe from BOC Pra-Leu OMe. A number of new propargylglycine derivatives are reported.
- Fauchere,Leukart,Eberle,Schwyzer
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p. 1385 - 1395
(2007/10/06)
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