- Nitroimidazole compound as well as preparation method and application thereof
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The invention discloses a novel nitroimidazole compound as well as a preparation method and application thereof. The nitroimidazole compound has a general formula (I) shown in the specification.
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Paragraph 0377-0379; 0380-0381
(2021/02/10)
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- Application of Flow and Biocatalytic Transaminase Technology for the Synthesis of a 1-Oxa-8-azaspiro[4.5]decan-3-amine
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Spirocyclic ring systems are useful intermediates in the design and synthesis of medicinally active agents and commonly found as cores in natural products. Recently, syntheses of a key intermediate Boc-protected-1-oxa-8-azaspiro[4.5]decan-3-amine 1 were examined. While multigram quantities of the racemic material could be made from the reduction of an energic azide intermediate, larger scale reactions and a chiral synthesis required further investigations. Herein, we describe the use of a continuous three-step flow process to scale the formation and reduction of an azide intermediate, and the use of a transaminase to prepare the desired enantiomer in high yield and enantiomeric excess.
- Burns, Michael,Dorff, Peter H.,Kohrt, Jeffrey T.,Kumar, Rajesh,Lall, Manjinder S.,Lee, Chewah,Maguire, Robert J.,O'Neil, Steven V.,Price, Loren,Wagenaar, Melissa
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- Catalytic Regioselective Olefin Hydroarylation(alkenylation) by Sequential Carbonickelation-Hydride Transfer
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Alkene hydrocarbofunctionalization represents one of the most important classes of chemical transformations, but related branched-selective examples with unactivated olefins are scarce. Here, we report that catalytic amounts of a dimeric Ni(I) complex and an exogenous alkoxide base promote Markovnikov-selective hydroarylation(alkenylation) of unactivated and activated olefins using organo bromides or triflates derived from widely available phenols and ketones. Products bearing aryl- and alkenyl-substituted tertiary and quaternary centers could be isolated in up to 95% yield and >99:1 regioisomeric ratios. Contrary to previous dual-catalytic methods that rely on metal-hydride atom transfer (MHAT) to the olefin prior to carbofunctionalization with a cocatalyst, our mechanistic evidence points toward a nonradical reaction pathway that begins with site-selective carbonickelation across the C═C bond followed by hydride transfer using alkoxide as the hydride source. Utility of the single-catalyst protocol is highlighted through the synthesis of medicinally relevant scaffolds.
- Liu, Chen-Fei,Luo, Xiaohua,Wang, Hongyu,Koh, Ming Joo
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supporting information
p. 9498 - 9506
(2021/07/19)
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- CYCLOPROPYLAMINE COMPOUND AS LSD1 INHIBITOR AND USE THEREOF
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Provided is a cyclopropylamine compound as lysine-specific demethylase 1 (LSD1) inhibitor, and a use thereof in preparation of drug for treating diseases associated with LSD1. The cyclopropylamine compound is a compound represented by formula (I), an isomer thereof, and a pharmaceutically acceptable salt thereof.
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Paragraph 0179-0181
(2021/07/24)
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- Enantioselective Allylation Using Allene, a Petroleum Cracking Byproduct
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Allene (C3H4) gas is produced and separated on million-metric-ton scale per year during petroleum refining but is rarely employed in organic synthesis. Meanwhile, the addition of an allyl group (C3H5) to ketones is among the most common and prototypical reactions in synthetic chemistry. Herein, we report that the combination of allene gas with inexpensive and environmentally benign hydrosilanes, such as PMHS, can serve as a replacement for stoichiometric quantities of allylmetal reagents, which are required in most enantioselective ketone allylation reactions. This process is catalyzed by copper salts and commercially available ligands, operates without specialized equipment or pressurization, and tolerates a broad range of functional groups. Furthermore, the exceptional chemoselectivity of this catalyst system enables industrially relevant C3 hydrocarbon mixtures of allene with methylacetylene and propylene to be applied directly.
- Liu, Richard Y.,Zhou, Yujing,Yang, Yang,Buchwald, Stephen L.
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supporting information
p. 2251 - 2256
(2019/03/05)
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- Facile Preparation of Spirolactones by an Alkoxycarbonyl Radical Cyclization–Cross-Coupling Cascade
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An alkoxycarbonyl radical cyclization–cross-coupling cascade has been developed that allows functionalized γ-butyrolactones to be prepared in one step from simple tertiary alcohol-derived homoallylic oxalate precursors. The reaction succeeds with aryl and vinyl electrophiles and is compatible with heterocyclic fragments in both coupling partners. This chemistry allows for the rapid construction of spirolactones, which are of interest in drug discovery endeavors.
- Weires, Nicholas A.,Slutskyy, Yuriy,Overman, Larry E.
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supporting information
p. 8561 - 8565
(2019/05/22)
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- Easy-To-Synthesize Spirocyclic Compounds Possess Remarkable in Vivo Activity against Mycobacterium tuberculosis
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Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits, and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogues. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome.
- Guardia, Ana,Baiget, Jessica,Cacho, Mónica,Pérez, Arancha,Ortega-Guerra, Montserrat,Nxumalo, Winston,Khanye, Setshaba D.,Rullas, Joaquín,Ortega, Fátima,Jiménez, Elena,Pérez-Herrán, Esther,Fraile-Gabaldón, María Teresa,Esquivias, Jorge,Fernández, Raquel,Porras-De Francisco, Esther,Encinas, Lourdes,Alonso, Marta,Giordano, Ilaria,Rivero, Cristina,Miguel-Siles, Juan,Osende, Javier G.,Badiola, Katrina A.,Rutledge, Peter J.,Todd, Matthew H.,Remui?án, Modesto,Alemparte, Carlos
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p. 11327 - 11340
(2019/01/08)
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- TOLL-LIKE RECEPTOR-7 AGONIST
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Disclosed are a novel pyrrolopyrimidine ring compound as a TLR7 agonist or a pharmaceutically acceptable salt thereof, used for preventing or treating allergic rhinitis and asthma. In particular, disclosed is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
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Paragraph 0191
(2018/06/09)
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- DUAL NAV1.2/5HT2A INHIBITORS FOR TREATING CNS DISORDERS
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Compounds of formula I: I are disclosed, as are pharmaceutical compositions containing such compounds. Methods of treating neurological or psychiatric disorders in a patient in need are also disclosed. Such disorders include depression, bipolar disorder, pain, schizophrenia, obsessive compulsive disorder, addiction, social disorder, attention deficit hyperactivity disorder, an anxiety disorder, autism, a cognitive impairment, or a neuropsychiatric symptom such as apathy, depression, anxiety, psychosis, aggression, agitation, impulse control disorders, and sleep disorders in neurological disorders such as Alzheimer's and Parkinson's diseases.
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Paragraph 0320
(2018/03/28)
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- Development of Selective, Orally Active GPR4 Antagonists with Modulatory Effects on Nociception, Inflammation, and Angiogenesis
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A novel, selective, and efficacious GPR4 antagonist 13 was developed starting from lead compound 1a. While compound 1a showed promising efficacy in several disease models, its binding to a H3 receptor as well as a hERG channel prevented it from further development. Therefore, a new round of optimization addressing the key liabilities was performed and led to discovery of compound 13 with an improved profile. Compound 13 showed significant efficacy in the rat antigen induced arthritis as well as in the hyperalgesia and angiogenesis model at a well-tolerated dose of 30 mg/kg.
- Velcicky, Juraj,Miltz, Wolfgang,Oberhauser, Berndt,Orain, David,Vaupel, Andrea,Weigand, Klaus,Dawson King, Janet,Littlewood-Evans, Amanda,Nash, Mark,Feifel, Roland,Loetscher, Pius
-
supporting information
p. 3672 - 3683
(2017/05/17)
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- Preparation method of tert-butyl 2-iodomethyl-1-oxa-7-azaspirane [3,5] nonane-7-carboxylic ester
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The invention relates to a preparation method of tert-butyl 2-iodomethyl-1-oxa-7-azaspirane [3,5] nonane-7-carboxylic ester and mainly solves the technical problem that no appropriate industrial synthesis method exists at present. The method comprises two steps as follows: firstly, a compound 1 and a compound 2 produce a compound 3 under the action of zinc powder and ammonium chloride, then the compound 3 reacts with iodine and sodium bicarbonate in acetonitrile, a compound 4 is obtained, and the equation is shown in the specification. The compound obtained with the method is a useful intermediate for synthesis of numerous drugs or product.
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Paragraph 0006
(2016/11/09)
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- Cyclic Ether Synthesis via Palladium-Catalyzed Directed Dehydrogenative Annulation at Unactivated Terminal Positions
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Here, a palladium-catalyzed functionalization of unactivated sp3 C-H bonds with internal alcohol nucleophiles is described. Directed by an oxime-masked alcohol, annulation chemoselectively occurs at the β position, leading to a range of aliphatic cyclic ethers with four- to seven-membered rings. Tethered primary, secondary, and tertiary free hydroxyl groups can all react to give the corresponding cyclized products. In addition, benzyl and silyl protected alcohols can also be directly coupled. An sp3 C-H activation/intramolecular SN2 pathway was proposed.
- Thompson, Samuel J.,Thach, Danny Q.,Dong, Guangbin
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supporting information
p. 11586 - 11589
(2015/09/28)
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- THERAPEUTIC COMPOUNDS AND COMPOSITIONS
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Compounds of general formula (I) and compositions comprising compounds of general formula I that modulate pyruvate kinase are described herein. Also described herein are methods of using the compounds that modulate pyruvate kinase in the treatment of diseases.
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Page/Page column 165
(2014/09/29)
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- THERAPEUTIC COMPOUNDS AND COMPOSITIONS
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Compounds of general formula I: and compositions comprising compounds of general formula I that modulate pyruvate kinase are described herein. Also described herein are methods of using the compounds that modulate pyruvate kinase in the treatment of diseases.
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Paragraph 0667; 0668; 0669
(2014/09/30)
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- THERAPEUTIC COMPOUNDS AND COMPOSITIONS
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Compounds of general formula (I) and compositions comprising compounds of general formula (I) that modulate pyruvate kinase are described herein. Also described herein are methods of using the compounds that modulate pyruvate kinase in the treatment of diseases.
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Page/Page column 178; 179
(2014/09/29)
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- PYRAZOLO PYRIMIDINE DERIVATIVES
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The present invention relates to pyrazolo pyrimidine derivatives, to methods of preparing these, to combinations and pharmaceutical composition comprising these, and to their use in the treatment of diseases and disorders which may for example involve autoimmune diseases, angiogenesis, pain, and/or inflammatory diseases.
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Paragraph 0334-0335
(2013/03/26)
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- Synthesis of oxaspiropiperidines as a strategy for lowering logD
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The syntheses of four new spiropiperidines designed as polar analogs of methyl 2-(3-azaspiro[5.5]undec-an-9-yl)acetate are described.
- Cernak, Timothy,Dykstra, Kevin,Levorse, Dorothy,Verras, Andreas,Balkovec, James,Nargund, Ravi,DeVita, Robert
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scheme or table
p. 6457 - 6459
(2011/12/22)
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- 1-OXA-8-AZASPIRO [4, 5 ] DECANE- 8 -CARBOXAMIDE COMPOUNDS AS FAAH INHIBITORS
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Provided herein are 1-oxa-8-azaspiro[4.5]decane-8-carboxamide compounds of formula I wherein Ar1, Ar2, R1, R2, R3 and R4 are as defined herein and the pharmaceutically acceptable salts of such compounds useful in treating diseases or conditions associated with fatty acid amide hydrolase (FAAH) activity, conditions including acute pain, chronic pain, neuropathic pain, nociceptive pain, inflammatory pain, fibromyalgia, rheumatoid arthritis, inflammatory bowel disease, lupus, diabetes, allergic asthma, vascular inflammation, urinary incontinence, overactive bladder, emesis, cognitive disorders, anxiety, depression, sleeping disorders, eating disorders, movement disorders, glaucoma, psoriasis, multiple sclerosis, cerebrovascular disorders, brain injury, gastrointestinal disorders, hypertension, or cardiovascular disease.
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Page/Page column 25-26
(2010/07/10)
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- Benzopiperidine derivatives
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Benzopiperidine derivatives represented by formula (I), salts thereof or hydrates thereof, processes for producing the same and drugs comprising the same: wherein the variables are as described in the specification. These compounds are useful as drugs efficacious in the prevention and treatment of these various inflammatory diseases and immunologic diseases, such as rheumatoid arthritis, atopic dermatitis, psoriasis, asthma, and rejection reaction accompanying organ transplantation.
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- Cyclohexane derivatives and their use as therapeutic agents
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The present invention relates compounds of formula (I), wherein ring A is a phenyl or pyridyl ring; X represents a linker selected from the group consisting of formulae: (a), (b), (c), (d), and (e); and R1, R2, R3, R4, R5, R6, R7, R13, R14, R15, R16, R17, R21a and R21b are as defined herein. The compounds are of particular use in the treatment or prevention of depression, anxiety, pain, inflammation, migraine, emesis or postherpetic neuralgia.
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- Phthalazine derivatives and remedies for erectile dysfunction
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The present invention provides a phthalazine compound as a therapeutic agent for erectile dysfunction represented by the following formula, a pharmacologically acceptable salt thereof or a hydrate thereof: wherein R1and R2are the same as or different from each other and represent a halogen atom, a C1 to C4 alkyl group which may be substituted with a halogen atom, a C1 to C4 alkoxy group which may be substituted with a halogen atom or a cyano group; X represents a cyano group, a nitro group, a halogen atom, a hydroxyimino group which may be substituted or a heteroaryl group which may be substituted; Y represents a heteroaryl group, an aryl group which may be substituted, an alkynyl group which may substituted, an alkenyl group, an alkyl group, an optionally substituted saturated or unsaturated 4- to 8-membered amine ring, and the cyclic amine compound is a monocyclic compound, bicyclic compound or a spiro compound; l is an integer of 1 to 3; provided that the case where l is 1 or 2, X is a cyano group, a nitro group or a chlorine atom, R1is a chlorine atom, R2is a methoxy group and Y is a 5- or 6-membered amine ring substituted with a hydroxyl group is excluded.
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- N-acylsulfonamide apoptosis promoters
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N-Benzoyl arylsulfonamides having the formula are BCL-Xl inhibitors and are useful for promoting apoptosis. Also disclosed are BCL-Xl inhibiting compositions and methods of promoting apoptosis in a mammal.
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- N-Acylsulfonamide apoptosis promoters
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N-Benzoyl arylsulfonamides having the formula Are BCL-X1 inhibitors and are useful for promoting apoptosis. Also disclosed are BCL-X1 inhibiting compositions and methods of promoting apoptosis in a mammal.
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- Pyrrolidine modulators of chemokine receptor activity
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The present invention is directed to pyrrolidine compounds of the formula 1: (wherein R1, R2, R3, R4, R5, R6and n are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-5 and/or CCR-3.
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