- An Efficient and Scalable Synthesis of tert-Butyl (3aR,6aS)-5-Oxohexahydrocyclo penta[c]pyrrole-2(1H)-carboxylate: A Pharmacologically Important Intermediate
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Hexahydrocyclopentapyrrolone derivatives constitute an important class of bicycles, and it represents an essential pharmacophore for diversified pharmacological activities. A highly efficient process for the synthesis of tert-butyl(3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 1 has been developed. The improved process involves transformation of isoindole 4 to diacid 5, using an inexpensive KMnO4 mediated oxidative cleavage as a key step. The developed process was cost-effective, high yielding, kilogram scalable, and commercially viable for synthesis of 1.
- Bahekar, Rajesh H.,Jadav, Pradip A.,Goswami, Amitgiri D.,Shah, Hardik A.,Dave, Bhushan N.,Joshi, Darshan A.,Pethani, Jignesh P.,Patel, Dipam,Agarwal, Sameer,Desai, Ranjit C.
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Read Online
- Preparation method of chiral 5-(methylamino) hexahydrocyclopenta[c]pyrrole-2 (1H)-Boc mesylate
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The invention discloses a preparation method of (3aR, 5S, 6aS)-5-(methylamino) hexahydrocyclopenta [c] pyrrol-2(1H)-tert-butyl formate mesylate, and belongs to the field of synthesis of medical intermediates. The preparation method comprises the following
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- Purine derivative and preparation method and application thereof
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The invention discloses a purine derivative and a preparation method and application thereof, belongs to the technical field of medicines, and designs and synthesizes a series of purine derivatives and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs of the purine derivatives. Experiments show that the compound has outstanding anti-cell proliferation activity and DOT1L enzyme inhibition effect, shows good tumor growth inhibition activity in a tumor transplantation tumor model, and has a good application prospect.
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- Late-Stage Intermolecular Allylic C-H Amination
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Allylic amination enables late-stage functionalization of natural products where allylic C-H bonds are abundant and introduction of nitrogen may alter biological profiles. Despite advances, intermolecular allylic amination remains a challenging problem due to reactivity and selectivity issues that often mandate excess substrate, furnish product mixtures, and render important classes of olefins (for example, functionalized cyclic) not viable substrates. Here we report that a sustainable manganese perchlorophthalocyanine catalyst, [MnIII(ClPc)], achieves selective, preparative intermolecular allylic C-H amination of 32 cyclic and linear compounds, including ones housing basic amines and competing sites for allylic, ethereal, and benzylic amination. Mechanistic studies support that the high selectivity of [MnIII(ClPc)] may be attributed to its electrophilic, bulky nature and stepwise amination mechanism. Late-stage amination is demonstrated on five distinct classes of natural products, generally with >20:1 site-, regio-, and diastereoselectivity.
- Clark, Joseph R.,Dixon, Charlie F.,Feng, Kaibo,Han, Wei,Ide, Takafumi,Koch, Vanessa,Teng, Dawei,Wendell, Chloe I.,White, M. Christina
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p. 14969 - 14975
(2021/10/01)
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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 110; 111
(2020/01/11)
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- West request acid bei geleg sandbank and intermediate preparation method
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The invention relates to a preparation method of besigliptin and its intermediate, and concretely relates to a preparation method of an azadicyclic compound besigliptin and its key intermediate. The preparation method comprises the following steps: carrying out step a, step b and step c to prepare the key intermediate compound of formula VII, carryin gout isomer resolution and protective group removal on the compound of formula VII to obtain a compound of formula XV, coupling the compound of formula XV with the compound of formula XIII, and salifying to form a target compound I. The preparation method has the advantages of substantial reduction of the production cost, simple production flow, yield increase, and suitableness for industrial production.
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Paragraph 0051; 0060-0063
(2019/02/26)
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- Design, Synthesis, and Preclinical Efficacy of Novel Nonretinoid Antagonists of Retinol-Binding Protein 4 in the Mouse Model of Hepatic Steatosis
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Retinol-binding protein 4 (RBP4) serves as a transporter for all-trans-retinol (1) in the blood, and it has been proposed to act as an adipokine. Elevated plasma levels of the protein have been linked to diabetes, obesity, cardiovascular diseases, and nonalcoholic fatty liver disease (NAFLD). Recently, adipocyte-specific overexpression of RBP4 was reported to cause hepatic steatosis in mice. We previously identified an orally bioavailable RBP4 antagonist that significantly lowered RBP4 serum levels in Abca4-/- knockout mice with concomitant normalization of complement system protein expression and reduction of bisretinoid formation within the retinal pigment epithelium. We describe herein the discovery of novel RBP4 antagonists 48 and 59, which reduce serum RBP4 levels by >80% in mice upon acute oral dosing. Furthermore, 59 demonstrated efficacy in the transgenic adi-hRBP4 murine model of hepatic steatosis, suggesting that RBP4 antagonists may also have therapeutic utility for the treatment of NAFLD.
- Cioffi, Christopher L.,Racz, Boglarka,Varadi, Andras,Freeman, Emily E.,Conlon, Michael P.,Chen, Ping,Zhu, Lei,Kitchen, Douglas B.,Barnes, Keith D.,Martin, William H.,Pearson, Paul G.,Johnson, Graham,Blaner, William S.,Petrukhin, Konstantin
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p. 5470 - 5500
(2019/06/07)
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- Tyrosine Kinase Inhibitor And Uses Thereof
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Disclosed is a compound of Formula (I) or a pharmaceutically acceptable salt, ester, or solvate thereof, or their stereoisomers, which can be used as tyrosine kinase inhibitor. Also disclosed is a method for preparing the compound, a pharmaceutical composition and a kit comprising the compound, and uses of the compound. The compound can be used as tyrosine kinase inhibitor, or can be used to reduce or inhibit activity of EGFR or mutant thereof, such as EGFR mutant comprising T790M mutation, in a cell, or to treat and/or prevent a disease associated with overactivity of EGFR, such as cancer.
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Paragraph 0550-0551
(2017/05/15)
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- Bicyclic [3.3.0]-Octahydrocyclopenta[c]pyrrolo Antagonists of Retinol Binding Protein 4: Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease
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Antagonists of retinol-binding protein 4 (RBP4) impede ocular uptake of serum all-trans retinol (1) and have been shown to reduce cytotoxic bisretinoid formation in the retinal pigment epithelium (RPE), which is associated with the pathogenesis of both dry age-related macular degeneration (AMD) and Stargardt disease. Thus, these agents show promise as a potential pharmacotherapy by which to stem further neurodegeneration and concomitant vision loss associated with geographic atrophy of the macula. We previously disclosed the discovery of a novel series of nonretinoid RBP4 antagonists, represented by bicyclic [3.3.0]-octahydrocyclopenta[c]pyrrolo analogue 4. We describe herein the utilization of a pyrimidine-4-carboxylic acid fragment as a suitable isostere for the anthranilic acid appendage of 4, which led to the discovery of standout antagonist 33. Analogue 33 possesses exquisite in vitro RBP4 binding affinity and favorable drug-like characteristics and was found to reduce circulating plasma RBP4 levels in vivo in a robust manner (>90%).
- Cioffi, Christopher L.,Racz, Boglarka,Freeman, Emily E.,Conlon, Michael P.,Chen, Ping,Stafford, Douglas G.,Schwarz, Daniel M.C.,Zhu, Lei,Kitchen, Douglas B.,Barnes, Keith D.,Dobri, Nicoleta,Michelotti, Enrique,Cywin, Charles L.,Martin, William H.,Pearson, Paul G.,Johnson, Graham,Petrukhin, Konstantin
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p. 5863 - 5888
(2015/08/24)
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- OCTAHYDROCYCLOPENTAPYRROLES, THEIR PREPARATION AND USE
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The present invention provides Octahydrocyclopentapyrrole compounds having the structure: (structurally represented) wherein psi is absent or present, and when present is a bond; R1, R2, R3, R4, and R5 are each independently H, halogen, CF, or C1-C4 alkyl; R6 is absent or present, and when present is H, OH, or halogen; A is absent or present, and when present is C(O) or C(O)NH; B is substituted or unsubstituted monocycle, bicycle, heteromonocycle, heterobicycle, benzyl, CO2H or (C1-C4 alkyl)-CO2H, wherein when B is CO2H, then A is present and is C(O); and when psi is present, then R6 is absent and when psi is absent, then R6 is present, or a pharmaceutically acceptable salt thereof, for treatement of diseases characterized by excessive lipofuscin accumulation in the retina.
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- OCTAHYDROPYRROLOPYRROLES, THEIR PREPARATION AND USE
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The present invention provides compounds comprising variously substituted octahydropyrrolopyrroles, their synthesis, methods of making, methods of using, compositions and formulations thereof.
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- Design, synthesis, and evaluation of nonretinoid retinol binding protein 4 antagonists for the potential treatment of atrophic age-related macular degeneration and stargardt disease
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Accumulation of lipofuscin in the retina is associated with pathogenesis of atrophic age-related macular degeneration and Stargardt disease. Lipofuscin bisretinoids (exemplified by N-retinylidene-N-retinylethanolamine) seem to mediate lipofuscin toxicity. Synthesis of lipofuscin bisretinoids depends on the influx of retinol from serum to the retina. Compounds antagonizing the retinol-dependent interaction of retinol-binding protein 4 (RBP4) with transthyretin in the serum would reduce serum RBP4 and retinol and inhibit bisretinoid formation. We recently showed that A1120 (3), a potent carboxylic acid based RBP4 antagonist, can significantly reduce lipofuscin bisretinoid formation in the retinas of Abca4-/-mice. As part of the NIH Blueprint Neurotherapeutics Network project we undertook the in vitro exploration to identify novel conformationally flexible and constrained RBP4 antagonists with improved potency and metabolic stability. We also demonstrate that upon acute and chronic dosing in rats, 43, a potent cyclopentyl fused pyrrolidine antagonist, reduced circulating plasma RBP4 protein levels by approximately 60%.
- Cioffi, Christopher L.,Dobri, Nicoleta,Freeman, Emily E.,Conlon, Michael P.,Chen, Ping,Stafford, Douglas G.,Schwarz, Daniel M. C.,Golden, Kathy C.,Zhu, Lei,Kitchen, Douglas B.,Barnes, Keith D.,Racz, Boglarka,Qin, Qiong,Michelotti, Enrique,Cywin, Charles L.,Martin, William H.,Pearson, Paul G.,Johnson, Graham,Petrukhin, Konstantin
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p. 7731 - 7757
(2015/01/09)
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- DIHYDROPTERIDINONE DERIVATIVES, PREPARATION PROCESS AND PHARMACEUTICAL USE THEREOF
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Dihydroperidinone derivatives, preparation process and pharmaceutical use thereof are disclosed. Specially, new dihydroperidinone derivatives represented by general formula (I), wherein each substituent of the general formula (I) is defined as in the description, their preparation process, pharmaceutical compositions comprising said derivatives and their use as therapeutical agents, especially as Plk kinase inhibitors are disclosed.
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- DIHYDROPTERIDINONE DERIVATIVES, PREPARATION PROCESS AND PHARMACEUTICAL USE THEREOF
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Dihydroperidinone derivatives, preparation process and pharmaceutical use thereof are disclosed. Specially, new dihydroperidinone derivatives represented by general formula (I), wherein each substituent of the general formula (I) is defined as in the description, their preparation process, pharmaceutical compositions comprising said derivatives and their use as therapeutical agents, especially as Plk kinase inhibitors are disclosed.
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- Evaluation of a 3-amino-8-azabicyclo[3.2.1]octane replacement in the CCR5 antagonist maraviroc
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The bicyclic 5-amino-3-azabicyclo[3.3.0]octanes were shown to be effective replacements for the 3-amino-8-azabicyclo[3.2.1]octane found in the CCR5 antagonist maraviroc.
- Lemoine, Rémy C.,Petersen, Ann C.,Setti, Lina,Baldinger, Thomas,Wanner, Jutta,Jekle, Andreas,Heilek, Gabrielle,deRosier, André,Ji, Changhua,Rotstein, David M.
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scheme or table
p. 1674 - 1676
(2010/07/03)
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- Azabicyclic compounds are central nervous system active agents
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Compounds of formula (I) are novel CNS active agents that are useful for treating pain and for treating other disorders associated with the cholinergic system.
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- Cobalt Nanoparticles on Charcoal: A Versatile Catalyst in the Pauson-Khand Reaction, Hydrogenation, and the Reductive Pauson-Khand Reaction
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(Matrix Presented) Dispersions of nanometer-sized cobalt particles with very high stability were prepared in charcoal and analyzed by electron microscopy and X-ray analysis. The resulting cobalt nanoparticles on charcoal (CNC) were successfully used as a catalyst for the carbonylative cycloaddition of alkyne, alkene, and carbon monoxide (Pauson-Khand reaction), hydrogenation, and the reductive Pauson-Khand reaction.
- Son, Seung Uk,Park, Kang Hyun,Chung, Young Keun
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p. 3983 - 3986
(2007/10/03)
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- Use of methyl 2-iodo-2-(phenylsulfonyl)-4-pentenoate in atom-transfer radical cyclizations. Entry into annulation products containing carbonyl or exo-methylene functionality
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Methyl 2-iodo-2-(phenylsulfonyl)-4-pentenoate (8) is reacted with N-BOC-allylamine to afford substituted 3-azabicyclo-[3.3.0]octanes (10) in a process which involves an initial iodine atom-transfer annulation followed by an ionic cyclization. The geminal carbomethoxy and phenylsulfonyl groups are then efficiently converted to either an exocyclic olefin or to a carbonyl group. The latter transformation allows phenylsulfonylacetates to be used as surrogates for acyl radicals in synthesis.
- Flynn,Zabrowski,Nosal
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p. 7281 - 7282
(2007/10/02)
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