- Synthesis of Azanucleosides by Anodic Oxidation in a Lithium Perchlorate–Nitroalkane Medium and Diversification at the 4′-Nitrogen Position
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Azanucleosides, in which the 4′-oxygen atom has been replaced with a nitrogen atom, have drawn much attention owing to their anticancer and antivirus activity, and tolerance towards nucleases. However, the traditional synthetic strategy requires multiple steps and harsh conditions, thereby limiting the structural and functional diversity of the products. Herein we describe the synthesis of azanucleosides by an electrochemical reaction in a lithium perchlorate–nitroethane medium, followed by postmodification at the 4′-N position. N-Acryloyl prolinol derivatives were converted into azanucleosides by anodic activation of the N-α-C?H bond. Moreover, the use of nitroethane instead of nitromethane lowered the oxidation potential of the N-acryloyl prolinols and increased the Faradic yield. The prepared azanucleosides were efficiently functionalized at the 4′-N-acryloyl group with a lipophilic alkanethiol and a fluorescent dye by conjugate addition and olefin cross-metathesis, respectively.
- Shoji, Takao,Kim, Shokaku,Chiba, Kazuhiro
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- Intramolecular hydrogen bond-controlled prolyl amide isomerization in glucosyl 3′(S)-hydroxy-5′-hydroxymethylproline hybrids: Influence of a C-5′-hydroxymethyl substituent on the thermodynamics and kinetics of prolyl amide cis/trans isomerization
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(Chemical Equation Presented) Peptide mimics containing spirocyclic glucosyl-(3′-hydroxy-5′-hydroxymethyl)proline hybrids (Glc3′(S)-5′(CH2OH)HypHs) with a polar hydroxymethyl substituent at the C-5′ position, such as C-terminal ester Ac-Glc3′(S
- Zhang, Kaidong,Teklebrhan, Robel B.,Schreckenbach,Wetmore, Stacey,Schweizer, Frank
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- Stereodivergent Synthesis of 3-Hydroxyprolines and 3-Hydroxypipecolic Acids via Ketoreductase-Catalyzed Dynamic Kinetic Reduction
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We report a practical enzymatic approach for the stereoselective synthesis of hydroxylated cyclic amino acids. Using ketoreductases, cyclic ketoesters are converted with high diastereo- and enantioselectivity to all isomers of 3-hydroxyproline and 3-hydroxypipecolic acid via a dynamic kinetic reduction reaction. This work highlights the ability of enzymes to provide solutions to challenges in stereoselective synthesis. (Figure presented.).
- Prier, Christopher K.,Lo, Michael M.-C.,Li, Hongming,Yasuda, Nobuyoshi
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supporting information
p. 5140 - 5143
(2019/11/03)
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- ARGINASE INHIBITORS AND METHODS OF USE
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Described herein are compounds of Formula I or a pharmaceutically acceptable salt thereof. The compounds of Formula I act as arginase inhibitors and can be useful in preventing, treating or acting as a remedial agent for arginase-related diseases.
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Page/Page column 248
(2019/10/04)
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- Synthesis and Microbiological Evaluation of Novel Tetracyclic Fluoroquinolones
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Conformationally constrained tetracyclic fluoroquinolones (FQs) were synthesized and profiled for their microbiological spectrum. The installation of a seven-membered ring between the pyrrolidine substituents and the C8 position on the FQ core scaffold resulted in a remarkable enhancement of microbiological potency toward both Gram-positive and Gram-negative bacteria. Focused optimization of seven-membered ring composition, stereochemistry, and amine placement led to the discovery of the two lead compounds that were selected for further progression.
- Wagman, Allan S.,Cirz, Ryan,McEnroe, Glenn,Aggen, James,Linsell, Martin S.,Goldblum, Adam A.,Lopez, Sara,Gomez, Marcela,Miller, George,Simons, Lloyd J.,Belliotti, Thomas R.,Harris, Christina R.,Poel, Toni-Jo,Melnick, Michael J.,Gaston, Ricky D.,Moser, Heinz E.
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p. 1687 - 1692
(2017/10/09)
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- COMBINATION OF CHIMERIC ANTIGEN RECEPTOR THERAPY AND AMINO PYRIMIDINE DERIVATIVES
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The invention provides compositions and methods for treating diseases associated with expression of CD19, e.g., by administering a recombinant T cell comprising the CD19 CAR as described herein, in combination with a BTK inhibitor, e.g., an amino pyrimidi
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Page/Page column 280; 281
(2017/04/29)
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- NOVEL AMINO PYRIMIDINE DERIVATIVES
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The present invention describes new amino pyrimidine derivatives and pharmaceutically acceptable salts thereof which appear to interact with Bruton's tyrosine kinase (Btk). Accordingly, the novel amino pyrimidines may be effective in the treatment of autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection, cancers e.g. of hematopoietic origin or solid tumors.
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Paragraph 0369; 0370; 0371
(2015/06/10)
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- NOVEL AMINO PYRIMIDINE DERIVATIVES
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The present invention describes new amino pyrimidine derivatives of formula (I) and pharmaceutically acceptable salts thereof which appear to interact with Bruton's tyrosine kinase (Btk). Accordingly, the novel amino pyrimidines may be effective in the treatment of autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection, cancers e.g. of hematopoietic origin or solid tumors.
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Page/Page column 77; 78
(2015/06/11)
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- ANTIBACTERIAL AGENTS
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Antibacterial compounds of formula (I) are provided, as well as stereoisomers and pharmaceutically acceptable salts and esters thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of such compounds.
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Page/Page column 62; 63
(2014/10/18)
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- L-Proline derived nitrogenous steroidal systems: An asymmetric approach to 14-azasteroids
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An efficient chiral pool approach using l-proline to access 14-azasteroids under mild reaction conditions has been described. The key step involves the intramolecular SN2′ cyclization reaction for the construction of critical C-ring in the nitrogen impregnated steroidal architectures bearing unsaturation at Δ9(11) position. In the endeavour to synthesize some new congeners, the remote electronic impact of the electron donating groups in A ring and heteroatoms like oxygen in B ring, on the propensity of C-ring cyclization was also observed.
- Singh, Ritesh,Panda, Gautam
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p. 19533 - 19544
(2013/10/22)
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- IAP INHIBITORS
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The present invention describes compounds, processes for their preparation, pharmaceutical compositions containing them, and their use in therapy.
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Page/Page column 39-40
(2011/06/25)
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- N-HYDROXYAMIDE DERIVATIVES POSSESSING ANTIBACTERIAL ACTIVITY
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Described herein are N-hydroxyamlde antibacterial compounds, methods for making the compounds, pharmaceutical compositions containing the compounds and methods of treating bacterial infections utilizing the compounds and pharmaceutical compositions compound of Formula (I): or a salt, solvate ti hydrate thereof, wherein A is (a) eachindicates a point of attachment.
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Page/Page column 16; 33; 36
(2010/02/17)
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- IAP INHIBITORS
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The present invention describes compounds, processes for their preparation, pharmaceutical compositions containing them, and their use in therapy.
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Page/Page column 38-39
(2010/12/26)
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- IAP INHIBITORS
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The present invention describes compounds, processes for their preparation, pharmaceutical compositions containing them, and their use in therapy.
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Page/Page column 66
(2010/04/25)
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- IAP INHIBITORS
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The present invention describes compounds, processes for their preparation, pharmaceutical compositions containing them, and their use in therapy.
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Page/Page column 99-100
(2010/12/26)
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- ANTIBACTERIAL FLUOROQUINOLONE ANALOGS
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Compounds having antibacterial activity are disclosed. The compunds have the following structure (I): including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein A, B, D, E, G, R1, R2, R3, R4, R5, R6 and R7 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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- IAP INHIBITORS
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The present invention describes compounds of the following formula: processes for their preparation, pharmaceutical compositions containing them, and their use in therapy. The compounds of the present invention inhibit IAPs (inhibitors of apoptosis protei
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Page/Page column 31
(2009/09/05)
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- A general route to cyclopeptide alkaloids: total syntheses and biological evaluation of paliurines e and F, ziziphines N and Q, abyssenine A, mucronine E, and analogues
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A full account of the total syntheses of the cyclopeptide alkaloids paliurine E and F, ziziphine N and Q, abyssenine A, and mucronine E is provided. A key feature of the syntheses involves an intramolecular amidation of a vinyl iodide, which allows us sim
- Toumi, Mathieu,Rincheval, Vincent,Young, Ashley,Gergeres, Danielle,Turos, Edward,Couty, Francois,Mignotte, Bernard,Evano, Gwilherm
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experimental part
p. 3368 - 3386
(2011/02/28)
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- First synthesis of 2,6-diazabicyclo[3.2.0]heptane derivatives
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The first synthesis of 6-phenyl-2,6-diazabicyclo[3.2.0]heptane 1 and its orthogonally protected precursor 2 is herein reported. Our strategy enables to chemically address the two nitrogen atoms of 2,6-diazabicyclo[3.2.0]heptane core individually and selectively, thus allowing rapid access to several subsets of widely substituted fused azetidines.
- Napolitano, Carmela,Borriello, Manuela,Cardullo, Francesca,Donati, Daniele,Paio, Alfredo,Manfredini, Stefano
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scheme or table
p. 7280 - 7282
(2010/03/03)
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- DIMERIC IAP INHIBITORS
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Smac mimetics that inhibit IAPs.
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Page/Page column 16
(2008/06/13)
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- AZA-BENZOFURANYL COMPOUNDS AND METHODS OF USE
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The invention relates to azabenzofuranyl compounds of Formula (I) with anti-cancer and/or anti-inflammatory activity and more specifically to azabenzofuranyl compounds which inhibit MEK kinase activity. The invention provides compositions and methods useful for inhibiting abnormal cell growth or treating a hyperproliferative disorder, or treating an inflammatory disease in a mammal. The invention also relates to methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.
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Page/Page column 131
(2008/06/13)
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- VLA-4 INHIBITOR
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An object of the present invention is to provide a compound which selectively inhibits binding of a ligand and ±421 integrin (VLA-4), a process for producing the compound, and a medicament containing the compound. A compound represented by the formula (I) etc. orasaltthereof, a process for producing the compound or a salt thereof, a medicament containing the compound or a salt thereof, as well as a preventive and/or a therapeutic agent for a disease caused by cell adhesion, for example, inflammatory reaction, autoimmune disease, cancer metastasis, bronchial asthma, nasal obstruction, diabetes, arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease and rejection reaction at transplantation, containing the compound or a salt thereof as a primary component. [wherein Y 1 represents a divalent aryl group etc. , V 1 represents an aryl group etc., and R 11 to R 14 represent H, OH or a halogen atom etc.]
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- Discovery of potent and muscle selective androgen receptor modulators through scaffold modifications
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A novel series of imidazolin-2-ones were designed and synthesized as highly potent, orally active and muscle selective androgen receptor modulators (SARMs), with most of the compounds exhibiting low nM in vitro potency in androgen receptor (AR) binding and functional assays. Once daily oral treatment with the lead compound 11a (AR Ki = 0.9 nM, EC50 = 1.8 nM) for 14 days induced muscle growth with an ED50 of 0.09 mg/kg, providing approximately 50-fold selectivity over prostate growth in an orchidectomized rat model. Pharmacokinetic studies in rats demonstrated that the lead compound 11a had oral bioavailability of 65% and a plasma half-life of 5.5 h. On the basis of their preclinical profiles, the SARMs in this series are expected to provide beneficial anabolic effects on muscle with minimal androgenic effects on prostate tissue.
- Li, James J.,Sutton, James C.,Nirschl, Alexandra,Zou, Yan,Wang, Haixia,Sun, Chongqing,Pi, Zulan,Johnson, Rebecca,Krystek Jr., Stanley R.,Seethala, Ramakrishna,Golla, Rajasree,Sleph, Paul G.,Beehler, Blake C.,Grover, Gary J.,Fura, Aberra,Vyas, Viral P.,Li, Cindy Y.,Gougoutas, Jack Z.,Galella, Michael A.,Zahler, Robert,Ostrowski, Jacek,Hamann, Lawrence G.
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p. 3015 - 3025
(2008/02/06)
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- Discovery of potent, orally-active, and muscle-selective androgen receptor modulators based on an N-aryl-hydroxybicyclohydantoin scaffold
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A novel, N-aryl-bicyclohydantoin selective androgen receptor modulator scaffold was discovered through structure-guided modifications of androgen receptor antagonists. A prototype compound (7R,7aS)-10b from this series is a potent and highly tissue-selective agonist of the androgen receptor. After oral dosing in a rat atrophied levator ani muscle model, (7R,7aS)-10b demonstrated efficacy at restoring levator ani muscle mass to that of intact controls and exhibited >50-fold selectivity for muscle over prostate.
- Sun, Chongqing,Robl, Jeffrey A.,Wang, Tammy C.,Huang, Yanting,Kuhns, Joyce E.,Lupisella, John A.,Beehler, Blake C.,Golla, Rajasree,Sleph, Paul G.,Seethala, Ramakrishna,Fura, Aberra,Krystek Jr., Stanley R.,An, Yongmi,Malley, Mary F.,Sack, John S.,Salvati, Mark E.,Grover, Gary J.,Ostrowski, Jacek,Hamann, Lawrence G.
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p. 7596 - 7599
(2007/10/03)
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- Stereoelectronic and steric effects in the collagen triple helix: Toward a code for strand association
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Collagen is the most abundant protein in animals. The protein consists of a helix of three strands, each with sequence X-Y-Gly. Natural collagen is most stable when X is (2S)-proline (Pro) and Y is (2S,4R)-4-hydroxyproline (4R-Hyp). We had shown previously that triple helices in which X is (2S,4S)-4- fluoroproline (4S-Flp) or Y is (2S,4R)-4-fluoroproline (4R-Flp) display hyperstability. This hyperstability arises from stereoelectronic effects that preorganize the main-chain dihedral angles in the conformation found in the triple helix. Here, we report the synthesis of strands containing both 4S-Flp in the X-position and 4R-Flp in the Y-position. We find that these strands do not form a stable triple helix, presumably because of an unfavorable steric interaction between fluoro groups on adjacent strands. Density functional theory calculations indicate that (2S,3S)-3-fluoroproline (3S-Flp), like 4S-Flp, should preorganize the main chain properly for triple-helix formation but without a steric conflict. Synthetic strands containing 3S-Flp in the X-position and 4R-Flp in the Y-position do form a triple helix. This helix is, however, less stable than one with Pro in the X-position, presumably because of an unfavorable inductive effect that diminishes the strength of the interstrand 3S-FlpC=O...H-NGly hydrogen bond. Thus, other forces can counter the benefits derived from the proper preorganization. Although (Pro-Pro-Gly) 7 and (4S-Flp-4R-Flp-Gly)7 do not form stable homotrimeric helices, mixtures of these two peptides form stable heterotrimeric helices containing one (Pro-Pro-Gly)7 strand and two (4S-Flp-4R-Flp-Gly) 7 strands. This stoichiometry can be understood by considering the cross sections of the two possible heterotrimeric helices. This unexpected finding portends the development of a "code" for the self-assembly of determinate triple helices from two or three strands.
- Hodges, Jonathan A.,Raines, Ronald T.
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p. 15923 - 15932
(2007/10/03)
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- VLA-4 INHIBITOR
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A compound which selectively inhibits bonding between a ligand and α4β1 integrin (VLA-4); a process for producing the compound; and a medicine containing the compound. The compound is one represented by, e.g., the formula (I) or a salt thereof. Also provided is a preventive and/or therapeutic agent which contains the compound or salt as a major component and is effective against diseases attributable to cell adhesion, such as, e.g., inflammatory reaction, autoimmune disease, cancer metastasis, bronchial asthma, nasal obstruction, diabetes, arthritis, psoriasis, multiple sclerosis, inflammatory intestinal disease, and rejection reaction in transplantation. (In the formula, Y1 represents arylene, etc.; V1 represents aryl, etc.; and R11 to R14 each represents H, OH, halogeno, etc.)
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- MONOCYCLIC AND BICYCLIC LACTAMS AS FACTOR XA INHIBITORS
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The present application describes monocyclic and bicyclic lactams and derivatives thereof of Formulae (Ia-e); wherein one of one of T and T is carbonyl, thiocarbonyl, or sulfonyl or pharmaceutically acceptable salt forms thereof. Compounds of the pr
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- BICYCLIC MODULATORS OF ANDROGEN RECEPTOR FUNCTION
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The present invention relates to bicyclic compounds according to formula I, pharmaceutical compositions containing such compounds and methods of using such compounds in the treatment of androgen receptor-associated conditions, such as age-related diseases, for example sarcopenia, wherein R1, R2, R5, X, Y and n are defined herein.
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Page/Page column 17
(2008/06/13)
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- Bicyclic modulators of androgen receptor function
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The invention provides for a pharmaceutical composition capable of modulating the androgen receptor comprising a compound of formula I wherein the substitutents are as described herein. Further provided are methods of using such compounds for the treatment of nuclear hormone receptor-associated conditions, such as age related diseases, for example sarcopenia. Also provided are pharmaceutical compositions containing such compounds and processes for preparing some of the compounds of the invention.
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- BICYCLIC MODULATORS OF ANDROGEN RECEPTOR FUNCTION
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The invention provides compounds according to formula I wherein the substitutents are as described herein. Further provided are methods of using such compounds for the treatment of nuclear hormone receptor-associated conditions, such as age related diseases, for example sarcopenia. Also provided are pharmaceutical compositions containing such compounds and processes for preparing some of the compounds of the invention.
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- Short, highly efficient syntheses of protected 3-azido- and 4-azidoproline and their precursors
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matrix presented An improved synthesis of protected cis- and trans-3-azido-L-proline and cis- and frans-4-azido-L- and -D-proline is reported. These compounds have been synthesized from the corresponding hydroxyproline precursors using diphenylphosphoryl azide under Mitsunobu conditions. Short, highly efficient syntheses of these precursors are described, based on a new lactone-opening reaction and p-nitrobenzoate hydrolysis under very mild conditions.
- Gomez-Vidal, Jose A.,Silverman, Richard B.
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p. 2481 - 2484
(2007/10/03)
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- Synthesis of optically pure N-Boc-protected (2R,3R)- and (2R,3S)-3-fluoroprolines
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Non-protein amino acids (2R,3R)- and (2R,3S)-3-fluoroprolines were synthesized as novel probes for studying the cis/trans isomerization of the amino acyl-proline peptide bond. The N-Boc-protected target compounds were obtained as optically pure material s
- Demange, Luc,Cluzeau, Jér?me,Ménez, André,Dugave, Christophe
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p. 651 - 653
(2007/10/03)
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