- Discovery of Novel 1-Cyclopentenyl-3-phenylureas as Selective, Brain Penetrant, and Orally Bioavailable CXCR2 Antagonists
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CXCR2 has emerged as a therapeutic target for not only peripheral inflammatory diseases but also neurological abnormalities in the central nervous system (CNS). Herein, we describe the discovery of a novel 1-cyclopentenyl-3-phenylurea series as potent and CNS penetrant CXCR2 antagonists. Extensive SAR studies, wherein molecules' property forecast index (PFI) was carefully optimized for overall balanced developability profiles, led to the discovery of the advanced lead compound 68 with a desirable PFI. Compound 68 demonstrated good in vitro pharmacology with excellent selectivity over CXCR1 and other chemokine receptors. Rat and dog pharmacokinetics (PK) revealed good oral bioavailability, high oral exposure, and desirable elimination half-life of the compound in both species. In addition, the compound demonstrated dose-dependent efficacy in the in vivo pharmacology neutrophil infiltration "air pouch" model in rodents after oral administration. Further, compound 68 is a CNS penetrant molecule with high unbound fraction in brain tissue.
- Lu, Hongfu,Yang, Ting,Xu, Zhongmiao,Lin, Xichen,Ding, Qian,Zhang, Yueting,Cai, Xin,Dong, Kelly,Gong, Sophie,Zhang, Wei,Patel, Metul,Copley, Royston C. B.,Xiang, Jianing,Guan, Xiaoming,Wren, Paul,Ren, Feng
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supporting information
p. 2518 - 2532
(2018/03/26)
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- Compound with cell proliferative resistance activity, preparation method and application
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The invention relates to a compound with cell proliferative resistance activity, a preparation method and application. The invention discloses a compound with cell proliferative resistance activity, as shown in formula I, pharmaceutically acceptable salt
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Paragraph 0083; 0084; 0085; 0086
(2018/08/03)
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- Metal-Free Catalytic Approach for Allylic C-H Amination Using N-Heterocycles via sp3 C-H Bond Activation
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A versatile metal-free synthesis of allylic N-heterocycles has been developed using a TBAI/TBHP oxidation system. This general protocol could be applied for the C-N bond formation of electron-deficient phthalimides, imidazoles, triazoles, and sulfonamides
- Sun, Jinwei,Wang, Yi,Pan, Yi
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p. 8945 - 8950
(2015/09/28)
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- Copper-catalyzed oxidative dehydrogenative carboxylation of unactivated alkanes to allylic esters via alkenes
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We report copper-catalyzed oxidative dehydrogenative carboxylation (ODC) of unactivated alkanes with various substituted benzoic acids to produce the corresponding allylic esters. Spectroscopic studies (EPR, UV-vis) revealed that the resting state of the catalyst is [(BPI)Cu(O2CPh)] (1-O2CPh), formed from [(BPI)Cu(PPh3)2], oxidant, and benzoic acid. Catalytic and stoichiometric reactions of 1-O2CPh with alkyl radicals and radical probes imply that C-H bond cleavage occurs by a tert-butoxy radical. In addition, the deuterium kinetic isotope effect from reactions of cyclohexane and d12-cyclohexane in separate vessels showed that the turnover-limiting step for the ODC of cyclohexane is C-H bond cleavage. To understand the origin of the difference in products formed from copper-catalyzed amidation and copper-catalyzed ODC, reactions of an alkyl radical with a series of copper-carboxylate, copper-amidate, and copper-imidate complexes were performed. The results of competition experiments revealed that the relative rate of reaction of alkyl radicals with the copper complexes follows the trend Cu(II)-amidate > Cu(II)-imidate > Cu(II)-benzoate. Consistent with this trend, Cu(II)-amidates and Cu(II)-benzoates containing more electron-rich aryl groups on the benzamidate and benzoate react faster with the alkyl radical than do those with more electron-poor aryl groups on these ligands to produce the corresponding products. These data on the ODC of cyclohexane led to preliminary investigation of copper-catalyzed oxidative dehydrogenative amination of cyclohexane to generate a mixture of N-alkyl and N-allylic products.
- Tran, Ba L.,Driess, Matthias,Hartwig, John F.
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supporting information
p. 17292 - 17301
(2015/02/02)
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- A general catalytic hydroamidation of 1,3-dienes: Atom-efficient synthesis of N-allyl heterocycles, amides, and sulfonamides
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Transition-metal-catalyzed hydroamination reactions are sustainable and atom-economical C-N bond-forming processes. Although remarkable progress has been made in the inter- and intramolecular amination of olefins and 1,3-dienes, related intermolecular reactions of amides are still much less known. Control of the regioselectivity without analogous telomerization is the particular challenge in the catalytic hydroamidation of alkenes and 1,3-dienes. Herein, we report a general protocol for the hydroamidation of electron-deficient N-heterocyclic amides and sulfonamides with 1,3-dienes and vinyl pyridines in the presence of a catalyst derived from [{Pd(π-cinnamyl)Cl}2] and ligand L7 or L10. The reactions proceeded in good to excellent yield with high regioselectivity. The practical utility of our method is demonstrated by the hydroamidation of functionalized biologically active substrates. The high regioselectivity for linear amide products makes the procedure useful for the synthesis of a variety of allylic amides. Give me an N bond: A general palladium-catalyzed intermolecular hydroamidation of 1,3-dienes with electron-deficient N-heterocycles, amides, and sulfonamides proceeded with high regioselectivity for 1,4-addition and excellent functional-group tolerance (see scheme). The practical utility of the method was demonstrated by the hydroamidation of functionalized biologically active substrates. Copyright
- Banerjee, Debasis,Junge, Kathrin,Beller, Matthias
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supporting information
p. 1630 - 1635
(2014/03/21)
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- N-bromoimide/DBU combination as a new strategy for intermolecular allylic amination
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Allylic amination reactions of alkenes, with an NBP (N-bromophthalimide) or NBS (N-bromosuccinimide)/DBU combination, were developed, in which both internal and external nitrogen nucleophiles can be installed directly. Dual activation of NBS or NBP by DBU leads to more electrophilic bromine and more nucleophilic nitrogen atoms simultaneously. This protocol may provide a novel and complementary access to allylic amination under mild conditions.
- Wei, Ying,Liang, Fushun,Zhang, Xintong
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supporting information
p. 5186 - 5189
(2013/11/06)
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- SUBSTITUTED DIAMINOCARBOXAMIDE AND DIAMINOCARBONITRILE PYRIMIDINES, COMPOSITIONS THEREOF, AND METHODS OF TREATMENT THEREWITH
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Provided herein are Diaminopyrimidine Compounds having the following structures: wherein R1, R2, R3, and R4 are as defined herein, compositions comprising an effective amount of a Diaminopyrimidine Compound, and methods for treating or preventing liver fibrotic disorders or a condition treatable or preventable by inhibition of a JNK pathway.
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Page/Page column 118
(2012/11/07)
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- Structure-activity studies of a novel series of isoxazole-3-carboxamide derivatives as TRPV1 antagonists
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Optimisation of a screening hit incorporating both TRPV1 activity and solubility was conducted. Substitution of the isoxazole-3-carboxamide with the bespoke 1S, 3R-3-aminocyclohexanol motif afforded the requisite balance of potency and solubility. Compounds 32 and 40 were found to have antihyperalgesic effects in the rat CFA Hg assay and induce a mechanism based hyperthermia.
- Palin, Ronald,Abernethy, Lynn,Ansari, Nasrin,Cameron, Kenneth,Clarkson, Tom,Dempster, Maureen,Dunn, David,Easson, Anna-Marie,Edwards, Darren,MacLean, John,Everett, Katy,Feilden, Helen,Ho, Koc-Kan,Kultgen, Steve,Littlewood, Peter,McArthur, Duncan,McGregor, Deborah,McLuskey, Hazel,Neagu, Irina,Neale, Stuart,Nisbet, Lesley-Anne,Ohlmeyer, Michael,Pham, Quynhchi,Ratcliffe, Paul,Rong, Yajing,Roughton, Andrew,Sammons, Melanie,Swanson, Robert,Tracey, Heather,Walker, Glenn
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scheme or table
p. 892 - 898
(2011/03/21)
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- The stereodivergent aziridination of allylic carbamates, amides and sulfonamides
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A stereodivergent protocol for the aziridination of a range of cyclic allylic amine derivatives has been developed. syn-Products can be obtained in >99:1 dr under H-bonded control and anti-products are obtained in >99:1 dr under steric control by judiciou
- Davies, Stephen G.,Ling, Kenneth B.,Roberts, Paul M.,Russell, Angela J.,Thomson, James E.,Woods, Philip A.
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experimental part
p. 6806 - 6813
(2010/09/17)
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- Chemo- and diastereoselective cyclopropanation of allylic amines and carbamates
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A highly chemo- and diastereoselective protocol for the cyclopropanation of tertiary allylic amines with Shi's carbenoid [CF3CO 2ZnCH2I] is described. The high levels of diastereoselectivity observed in these reactions may be attributed to chelation of the nitrogen atom to the zinc reagent, which then transfers a methylene unit to the syn-face of the olefin. Furthermore, a stereodivergent protocol for the cyclopropanation of a range of allylic carbamates has been developed, which provides access to both diastereoisomers of the corresponding cyclopropanes with very high levels of diastereoselectivity: cyclopropanation with the Wittig-Furukawa reagent [Zn(CH2I)2] proceeds under chelation control to give the corresponding syn-product, whilst reaction with Shi's carbenoid proceeds under steric control to give the corresponding anti-cyclopropane, in >95:5 dr in both cases.
- Csatayová, Kristína,Davies, Stephen G.,Lee, James A.,Ling, Kenneth B.,Roberts, Paul M.,Russell, Angela J.,Thomson, James E.
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p. 8420 - 8440
(2010/12/20)
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- THALIDOMIDE ANALOGS
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Thalidomide analogs that modulate tumor necrosis factor alpha (TNF-α) activity and angiogenesis are disclosed. In particularly disclosed embodiments, the thalidomide analogs are isosteric sulfur-containing analogs. Also disclosed are methods of treating a subject with the analogs.
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Page/Page column 57
(2008/06/13)
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- Thiothalidomides: Novel Isosteric Analogues of Thalidomide with Enhanced TNF-α Inhibitory Activity
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Thalidomide is being increasingly used in the clinical management of a wide spectrum of immunologically-mediated and infectious diseases, and cancers. However, the mechanisms underlying its pharmacological action are still under investigation. In this regard, oral thalidomide is clinically valuable in the treatment of erythema nodosum leprosum (ENL) and mutiple myeloma and effectively reduces tumor necrosis factor-α (TNF-α) levels and angiogenesis in vivo. This contrasts with its relatively weak effects on TNF-α and angiogenesis in in vitro studies and implies that active metabolites contribute to its in vivo pharmacologic action and that specific analogues would be endowed with potent activity. Our focus in the structural modification of thalidomide is toward the discovery of novel isosteric active analogues. In this regard, a series of thiothalidomides and analogues were synthesized and evaluated for their TNF-α inhibitory activity against lipopolysacharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC), This was combined with a PBMC viability assay to differentiate reductions in TNF-α secretion from cellular toxicity. Two isosteric analogues of thalidomide, compounds 15 and 16, that mostly reflect the parent compound, together with the simple structure, dithioglutarimide 19, potently inhibited TNF-α secretion, compared to thalidomide, 1. The mechanism underpinning this most likely is posttranscriptional, as each of these compounds decreased TNF-α mRNA stability via its 3′-UTR. The potency of 19 warrants further study and suggests that replacement of the amide carbonyl with a thiocarbonyl may be beneficial for increased TNF-α inhibitory action. In addition, an intact phthalimido moiety appeared to be requisite for TNF-α inhibitory activity.
- Zhu, Xiaoxiang,Giordano, Tony,Yu, Qian-Sheng,Holloway, Harold W.,Perry, Tracy Ann,Lahiri, Debomoy K.,Brossi, Arnold,Greig, Nigel H.
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p. 5222 - 5229
(2007/10/03)
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- Nucleophilic Substitution Reactions of (Alkoxymethylene)dimethylammonium Chloride
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The use of imidate esters as potential replacements for diethyl azodicarboxylate and triphenylphosphine in the Mitsunobu reaction is described. A series of secondary alcohols were allowed to react with (chloromethylene)dimethylammonium chloride, generated from dimethylformamide (DMF) and oxalyl chloride, to give imidate esters. Reaction of these salts with potassium benzoate or potassium phthalimide gave the products of SN2 substitution in excellent yields with clean inversion of stereochemistry. Optimization of reaction conditions is discussed as a means to increase the atom economy of the process by minimizing the quantity of nucleophile required.
- Barrett, Anthony G. M.,Braddock, D. Christopher,James, Rachel A.,Koike, Nobuyuki,Procopiou, Panayiotis A.
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p. 6273 - 6280
(2007/10/03)
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- Nucleophilic substitution of (alkoxymethylene)dimethylammonium chloride with potassium phthalimide; a convenient procedure for the synthesis of imides with inversion of configuration
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Secondary alcohols are converted into their phthalimido derivatives with inversion of configuration via sequential reaction with (chloromethylene)dimethylammonium chloride and potassium phthalimide.
- Barrett, Anthony G. M.,Braddock, D. Christopher,James, Rachel A.,Procopiou, Panayiotis A.
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p. 433 - 434
(2007/10/03)
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- Stereocontrolled Preparation of Cyclohexane Amino Alcohols Utilising a Modified Mitsunobu Reaction
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A method for the introduction of amino groups into aliphatic systems is described.Cyclohex-2-enol reacts with aromatic diacylamines under Mitsunobu reaction conditions to give either N-alkylated or O-alkylated products in a controlled, predictable manner.
- Sammes, Peter G.,Thetford, Dean
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p. 655 - 661
(2007/10/02)
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- NEW ROUTES TO CIS-1,2-HYDROXYAMINES AND RELATED SYSTEMS
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Use of modified Mitsunobu reactions followed by intramolecular cyclisations have been used to prepare cis-1,2-hydroxyamines, cis-1,3-hydroxyamines, 1,2,3-dihydroxyamines and 1,2,3-diaminoalcohols from allylic alcohols
- Sammes, Peter G.,Thetford, Dean
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p. 2275 - 2278
(2007/10/02)
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