- Synthesis of enantiopure 3,5-disubstituted pyrrolidines by ring-opening/cross-metathesis reaction of 2-azanorbornene derivatives
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A concise method for the synthesis of enantiopure 3,5-disubstituted pyrrolidines from 2-azanorbornene derivatives is described. The method is also applied to the synthesis of 3,5-disubstituted prolines.
- Arjona, Odon,Cabas, Ma Jose,Nieto-Rubio, Jose,Querejeta, Ana
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- Squarate-based carbocyclic nucleosides: Syntheses, computational analyses and anticancer/antiviral evaluation
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Squaric acid and its derivatives are versatile synthons and have demonstrated applications in medicinal chemistry, notably as non-classical bioisosteric replacements for functional groups such as carboxylic acids, alpha-amino acids, urea, guanidine, peptide bonds and phosphate/pyrophosphate linkages. Surprisingly, no reports have appeared concerning its possible application as a nucleobase substitute in nucleosides. A preliminary investigation of such an application is reported herein. 3-Amino-4-((1R,4S)-4-(hydroxymethyl)cyclopent-2-en-1-yl)amino-cyclobut-3-ene-1,2-dione, 3-((1R,4S)-4-(hydroxymethyl)cyclopent-2-en-1-yl)amino-4-methoxycyclobut-3-ene-1,2-dione, and 3-hydroxy-4-((1R,4S)-4-(hydroxymethyl)cyclopent-2-en-1-yl)amino-cyclobut-3-ene-1,2-dione sodium salt were synthesized. Computational analyses of their structures and preliminary antitumor and antiviral screening results are reported.
- Lu, Meijun,Lu, Qing-Bin,Honek, John F.
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Read Online
- Synthesis and evaluation of cyclopentane-based muraymycin analogs targeting MraY
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Antibiotic resistance is one of the most challenging global health issues and presents an urgent need for the development of new antibiotics. In this regard, phospho-MurNAc-pentapeptide translocase (MraY), an essential enzyme in the early stages of peptid
- Kwak, Seung-Hwa,Lim, Won Young,Hao, Aili,Mashalidis, Ellene H.,Kwon, Do-Yeon,Jeong, Pyeonghwa,Kim, Mi Jung,Lee, Seok-Yong,Hong, Jiyong
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- COMPOUNDS TARGETING PRMT5
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Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same. Also provided herein are methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
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Paragraph 0217
(2021/10/11)
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- COMPOUNDS TARGETING PRMT5
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Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same. Also provided herein are methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
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Paragraph 0216
(2020/10/20)
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- PRMT5 INHIBITORS
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The present invention provides a compound of Formula (I) and the pharmaceutically acceptable salts, esters, and prodrugs thereof, which are PRMT5 inhibitors. Also provided are methods of making compounds of Formula I, pharmaceutical compositions comprising compounds of Formula I, and methods of using these compounds to treat cancer, sickle cell, and hereditary persistence of foetal hemoglobin (HPFH) mutations.
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Page/Page column 66-67
(2020/03/02)
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- Efficient and stereoselective synthesis of 2′-fluoro-6′-methylene-carbocyclic adenosine (FMCA)
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The invention provides a new convergent approach for the synthesis of 2′-fluoro-6′-methylene-carbocyclic adenosine (FMCA) from a readily available starting material (Vince lactam) in fourteen steps. An efficient and practical methodology for stereospecifi
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Page/Page column 20
(2016/06/01)
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- An expedient synthesis of oxazepino and oxazocino quinazolines
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A synthetic route to a new class of privileged tri- and tetra-cyclic quinazolines containing a medium-sized ring is reported. An expedient synthetic route involving nucleophilic aromatic substitution, and sequential Niementowski and BOP-mediated ring clos
- Hensbergen, Albertus Wijnand,Mills, Vanessa R.,Collins, Ian,Jones, Alan M.
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p. 6478 - 6483
(2015/11/16)
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- Stereoselective synthesis of 2′-fluoro-6′-methylene carbocyclic adenosine via Vince lactam
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2′-Fluoro-6′-methylene carbocyclic adenosine (FMCA) is a potent and selective inhibitor of wild type as well as drug-resistant hepatitis B virus (HBV) mutants. FMCA demonstrated excellent anti-HBV activity against both adefovir-resistant and lamivudine-re
- Singh, Uma S.,Mishra, Ram C.,Shankar, Ravi,Chu, Chung K.
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p. 3917 - 3923
(2014/05/20)
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- Chemoselective opening of Vince lactam epoxide with nitrogen nucleophiles
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Here is reported the chemoselective opening of the amide bond on a Vince lactam derivative with amines, without the cleavage of the epoxide-moiety, getting five new epoxides. Also reported is the rearrangement of the epoxides into the respective five new
- Giorgi, Gianluca,Guideri, Luca,Ponticelli, Fabio
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experimental part
p. 1463 - 1467
(2011/03/23)
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- Novel Tricyclic Compounds
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The invention provides a compound of Formula (I) pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variable are defined herein. The compounds of the invention are useful for treating immunological and oncological conditions.
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Page/Page column 66
(2009/12/27)
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- DIPEPTIDYL PEPTIDASE IV INHIBITOR COMPOUNDS AND COMPOSITIONS
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The present invention relates to dipeptidyl peptidase IV (DPP-IV) inhibitors of formula (1), pharmaceutical compositions containing them, processes for their preparation, and methods for treating disorders mediated by DPP-IV inhibition, such as diabetes, especially Type II diabetes, with them, wherein Rj is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl; R2 is hydrogen or Q-β alkyl; Y is -S(O)m, -CH2-, -CHF or CF2; R3 is hydrogen, nitrile (-CN), COOH, or an isostere of a carboxylic acid.
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Page/Page column 23
(2010/11/28)
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- NOVEL DIPEPTIDYL PEPTIDASE IV INHIBITORS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND PROCESS FOR THEIR PREPARATION
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The present invention relates to novel compounds useful as dipeptidyl peptidase IV (DPP-IV) inhibitors of the formula: (I) wherein Y is -S(O)m, -CH2-, CHF, or -CF2; m is 0, 1, or 2; X is a bond, C1-C5 alkyl (e.g., -CH2-), or -C(=0)-; the dotted line [----] in the carbocyclic ring represents an optional double bond; R1 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, CN, -COOR3, CONR3R4, -OR3, -NR3R4, or NR3COR3; R2 is hydrogen, cyano, COOH, or an isostere of a carboxylic acid (such as SO3H, CONOH, B(OH)2, PO3R3R4, SO2NR3R4, tetrazole, -COOR3, -CONR3R4, NR3COR4, or -COOCOR3).
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(2008/06/13)
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- NOVEL DIPEPTIDYL PEPTIDASE IV INHIBITORS; PROCESS FOR THEIR PREPARATION AND COMPOSITIONS CONTAINING THEM
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The present invention relates to novel organic compounds, more particularly, novel Dipeptidyl peptidase IV (DPP-IV) inhibitors of general formula (I) wherein: Y is -S(O)m-, -CH2-, -CHF-, or -CF2; X and Z are independently -C(=O)-, -NR3-, - O- or -S(O)m-; each occurrence of m is independently 0, 1 or 2; a is 0, 1 or 2; b is 0, 1 or 2; the dotted line [----] in the carbocyclic ring represents an optional double bond; R1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl; R2 is hydrogene, nitrile (-CN), COOH, or an isostere of carboxylic; or analogs, tautomers, enantiomers, diastereomers, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts, N-oxides, pharmaceutically acceptable solvates and pharmaceutical compositions containing them.
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Page/Page column 28-29
(2010/02/15)
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- Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives
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We report the application of phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes affect antiviral activity and metabolic stability. Separate and distinct SARs were noted for HIV and HBV. Additionally, ProTides were prepared from the D-nucleoside D-Cd4A and the dideoxy analogues L-CddA and D-CddA. These compounds showed more modest potency improvements over the parent drug. In conclusion, the ProTide approach is highly successful when applied to L-Cd4A with potency improvements in vitro as high as 9000-fold against HIV. With a view to preclinical candidate selection we carried out metabolic stability studies using cynomolgus monkey liver and intestinal S9 fractions.
- McGuigan, Christopher,Hassan-Abdallah, Alshaimaa,Srinivasan, Sheila,Wang, Yikang,Siddiqui, Adam,Daluge, Susan M.,Gudmundsson, Kristjan S.,Zhou, Huiqiang,McLean, Ed W.,Peckham, Jennifer P.,Burnette, Thimysta C.,Marr, Harry,Hazen, Richard,Condreay, Lynn D.,Johnson, Lance,Balzarini, Jan
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p. 7215 - 7226
(2007/10/03)
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- NOVEL DIPEPTIDYL PEPTIDASE IV INHIBITORS; PROCESSES FOR THEIR PREPARATION AND COMPOSITIONS THEREOF
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The present invention relates to novel dipeptidyl peptidase IV (DPP-IV) inhibitors or general formula (1) useful for treating diabetes, non-insulin dependent diabetes mellitus, impaired glucose tolerance, inflammatory bowel disease, ulcerative colitis,Chron’s disease, obesity, and metabolic syndrome.
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Page/Page column 29-30
(2008/06/13)
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- Base pairing and replicative processing of the formamidopyrimidine-dG DNA lesion
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The 2,6-diamino-4-hydroxy-5-formamidopyrimidine of 2′-deoxyguanosine (FaPydG) is one of the major DNA lesions found after oxidative stress in cells. To clarify the base pairing and coding potential of this major DNA lesion with the aim to estimate its mut
- Ober, Matthias,Mueller, Heiko,Pieck, Carsten,Gierlich, Johannes,Carell, Thomas
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p. 18143 - 18149
(2007/10/03)
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- Synthesis of stable and cell-type selective analogues of cyclic ADP-ribose, a Ca2+-mobilizing second messenger. Structure-activity relationship of the N1-ribose moiety
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We previously developed cyclic ADP-carbocyclic ribose (cADPcR, 2) as a stable mimic of cyclic ADP-ribose (cADPR, 1), a Ca2+-mobilizing second messenger. A series of the N1-ribose modified cADPcR analogues, designed as novel stable mimics of cAD
- Kudoh, Takashi,Fukuoka, Masayoshi,Ichikawa, Satoshi,Murayama, Takashi,Ogawa, Yasuo,Hashii, Minako,Higashida, Haruhiro,Kunerth, Svenja,Weber, Karin,Guse, Andreas H.,Potter, Barry V. L.,Matsuda, Akira,Shuto, Satoshi
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p. 8846 - 8855
(2007/10/03)
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- Process for preparing enantiomerically enriched N-derivatized lactams
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The present invention relates to a process for the preparation of enantiomerically enriched N-derivatized (1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-ones by use of an enzyme.
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- Highly selective directed hydrogenation of enantiopure 4-(tert-butoxycarbonylamino)cyclopent-1-enecarboxylic acid methyl esters
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The use of both N-tert-butoxycarbonylamino- and hydroxyl-directed hydrogenation methodology to yield essentially single diastereomers of 3-(tert-butoxycarbonylamino)-4-hydroxycyclopentanecarboxylic acid methyl esters and 3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid methyl esters is described. These results incorporate the first reported carbamate-directed hydrogenations of functionalised cyclopentenes.
- Smith, Mark E.B.,Derrien, Nadine,Lloyd, Michael C.,Taylor, Stephen J.C.,Chaplin, David A.,McCague, Raymond
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p. 1347 - 1350
(2007/10/03)
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- An efficient, scalable synthesis of the HIV reverse transcriptase inhibitor Ziagen (1592U89)
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Ziagen, (1S, cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2- cyclopentene-1-methanol, was synthesized from (1S,4R)-azabicyclo[2.2.1]hept- 5-en-3-one by efficient processes which bypass problematic steps in earlier routes. 2-Amino-4,6-dichloro-5-formamidopyrimidine is a key intermediate which makes possible an efficient construction of the purine from a chiral cyclopentenyl precursor.
- Daluge, Susan M.,Martin, Michael T.,Sickles, Barry R.,Livingston, Douglas A.
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p. 297 - 327
(2007/10/03)
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- A practical enzymatic procedure for the resolution of N-substituted 2- azabicyclo[2.2.1]hept-5-en-3-one
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A simple and efficient process for the enantioselective resolution of N- substituted 2-azabicyclo[2.2.1]hept-5-en-3-one has been developed using commercially available hydrolytic enzymes. This offers a practical approach for the preparation of enantiomerically pure N-substituted γ-lactams.
- Mahmoudian, Mahmoud,Lowdon, Andrew,Jones, Martin,Dawson, Michael,Wallis, Christopher
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p. 1201 - 1206
(2007/10/03)
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- Chirospecific Syntheses of Precursors of Cyclopentane and Cyclopentene Carbocyclic Nucleosides by -Coupling and Transannular Alkylation
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A new method is reported for the preparation of enantiomerically pure (1R,2S,4S)-1-amino-2-hydroxy-4-(hydroxymethyl)cyclopentane, (1R,2R,4S)-1-amino-2-fluoro-4-(hydroxymethyl)cyclopentane, and (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene, advanced precursors to carbocyclic nucleosides.The method involves initial conversion of D-serine into an aldehyde with 9-phenylfluorenyl protection at nitrogen and O-benzyl protection at oxygen.A -coupling of this aldehyde with a titanium homoenolate derived from tert-butyl 3-iodopropionate gave the corresponding anti-lactone in high yield.Regioselective hydrogenolysis of the amine protecting group, accompanied by intramolecular O- to N-cyclization formed a lactam.After suitable nitrogen protection and functional group manipulation, transannular alkylation afforded the corresponding 2-benzyl- or 2-(p-methoxybenzyl)-6-hydroxy-2-azabicyclo-3-heptanone.Functional group modification of the 2-benzyl analogue gave the resulting 6(S)-hydroxy and 6(R)-fluoro N-BOC imides; alternatively, the 2-(p-methoxybenzyl) analogue was converted to an N-BOC imide containing an olefinic linkage at C-5 and C-6 of the bicycle.Subjecting each of the N-BOC imides to a reduction-deprotection sequence than afforded the desired carbocyclic analogues.The -coupling method also allowed improved and expedient access to an advanced tribenzylated lactam previously used in the racemic syntheses of the hydroxylated alkaloids D-mannonolactam, deoxymannojirimycin, and prosopinone, providing a formal asymmetric synthesis of these alkaloids.
- Campbell, Jeffrey A.,Lee, Won Koo,Rapoport, Henry
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p. 4602 - 4616
(2007/10/02)
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- Development of the Biocatalytic Resolution of 2-azabicyclohept-5-en-3-one as an entry to Single-Enantiomer Carbocyclic Nucleosides
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For the resolution of the bicyclic lactam 2-azabicyclohept-5-en-3-one, efficient whole cell biocatalysts have been identified and from these, enzymes (lactamases) have been isolated.While the two enzymes obtained act on different enantiomers of the lactam, either can be used in scaleable processes to obtain synthons for carbocyclic nucleosides having the natural configuration.
- Taylor, Stephen J C,McCague, Raymond,Wisdom, Richard,Lee, Carol,Dickson, Karen,et al.
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p. 1117 - 1128
(2007/10/02)
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