- PREPARATION OF A CHK1 INHIBITOR COMPOUND
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The invention provides a novel synthetic route for the preparation of the Chk-1 inhibitor compound; also provided by the invention is a novel process for the preparation of the synthetic intermediate of formula (11); as well as novel process intermediates
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Page/Page column 28-29
(2021/06/22)
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- Tricyclic Indazoles - A Novel Class of Selective Estrogen Receptor Degrader Antagonists
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Herein, we report the identification and synthesis of a series of tricyclic indazoles as a novel class of selective estrogen receptor degrader antagonists. Replacement of a phenol, present in our previously reported tetrahydroisoquinoline scaffold, with an indazole group led to the removal of a reactive metabolite signal in an in vitro glutathione trapping assay. Further optimization, guided by X-ray crystal structures and NMR conformational work, varied the alkyl side chain and pendant aryl group and resulted in compounds with low turnover in human hepatocytes and enhanced chemical stability. Compound 9 was profiled as a representative of the series in terms of pharmacology and demonstrated the desired estrogen receptor α degrader-antagonist profile and demonstrated activity in a xenograft model of breast cancer.
- Scott, James S.,Bailey, Andrew,Buttar, David,Carbajo, Rodrigo J.,Curwen, Jon,Davey, Paul R. J.,Davies, Robert D. M.,Degorce, Sébastien L.,Donald, Craig,Gangl, Eric,Greenwood, Ryan,Groombridge, Sam D.,Johnson, Tony,Lamont, Scott,Lawson, Mandy,Lister, Andrew,Morrow, Christopher J.,Moss, Thomas A.,Pink, Jennifer H.,Polanski, Radoslaw
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supporting information
p. 1593 - 1608
(2019/02/14)
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- METHOD FOR THE PREPARATION OF (4S)-4-(4-CYANO-2-METHOXYPHENYL)-5-ETHOXY-2,8-DIMETHYL-1,4-DIHYDRO-1-6-NAPHTHYRIDINE-3-CARBOXAMIDE AND RECOVERY OF (4S)-4-(4-CYANO-2-METHOXYPHENYL)-5-ETHOXY-2,8-DIMETHYL-1,4-DIHYDRO-1-6-NAPHTHYRIDINE-3-CARBOXAMIDE BY ELECTROCHEMICAL METHODS
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The present invention relates to a novel process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (I) and recovering (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (I) proceeding from (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula ent-(I)
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- METHOD FOR THE PREPARATION OF (4S)-4-(4-CYANO-2-METHOXYPHENYL)-5-ETHOXY-2,8-DIMETHYL-1,4-DIHYDRO-1-6-NAPHTHYRIDINE-3-CARBOXAMIDE AND THE PURIFICATION THEREOF FOR USE AS AN ACTIVE PHARMACEUTICAL INGREDIENT
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The present invention relates to a novel and improved process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (I)
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Paragraph 0178-0182
(2018/09/16)
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- INDAZOLE DERIVATIVES THAT DOWN-REGULATE THE ESTROGEN RECEPTOR AND POSSESS ANTI-CANCER ACTIVITY
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The specification relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof. The specification also relates to processes and intermediates used for their preparation, pharmaceutical compositions containing them and their use in the treatment of cell proliferative disorders.
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Page/Page column 141-142
(2017/12/28)
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- Iterative design of a biomimetic catalyst for amino acid thioester condensation
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Herein, the design of a catalyst that combines lessons learned from peptide biosynthesis, enzymes, and organocatalysts is described. The catalyst features a urea scaffold for carbonyl recognition and elements of nucleophilic catalysis. In the presence of 10 mol % of the organocatalyst, the rate of peptide bond formation is accelerated by 10000-fold over the uncatalyzed reaction between Fmoc-amino acid thioesters and amino acid methyl esters.
- Wu, Huabin,Handoko,Raj, Monika,Arora, Paramjit S.
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supporting information
p. 5122 - 5125
(2017/11/06)
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- METHOD FOR THE PREPARATION OF (4S)-4-(4-CYANO-2-METHOXYPHENYL)-5-ETHOXY-2,8-DIMETHYL-1,4-DIHYDRO-1-6-NAPHTHYRIDINE-3-CARBOX-AMIDE AND THE PURIFICATION THEREOF FOR USE AS AN ACTIVE PHARMACEUTICAL INGREDIENT
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The present invention relates to a novel and improved process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (I) and also the preparation and use of the crystalline polymorph I of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (I).
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- 5-HT2A/5-HT2C Receptor Pharmacology and Intrinsic Clearance of N-Benzylphenethylamines Modified at the Primary Site of Metabolism
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The toxic hallucinogen 25B-NBOMe is very rapidly degraded by human liver microsomes and has low oral bioavailability. Herein we report on the synthesis, microsomal stability, and 5-HT2A/5-HT2C receptor profile of novel analogues of 25B-NBOMe modified at the primary site of metabolism. Although microsomal stability could be increased while maintaining potent 5-HT2 receptor agonist properties, all analogues had an intrinsic clearance above 1.3 L/kg/h predictive of high first-pass metabolism.
- Leth-Petersen, Sebastian,Petersen, Ida N.,Jensen, Anders A.,Bundgaard, Christoffer,B?k, Mathias,Kehler, Jan,Kristensen, Jesper L.
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p. 1614 - 1619
(2016/11/29)
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- Small molecule inhibitors of anthrax lethal factor toxin
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This manuscript describes the preparation of new small molecule inhibitors of Bacillus anthracis lethal factor. Our starting point was the symmetrical, bis-quinolinyl compound 1 (NSC 12155). Optimization of one half of this molecule led to new LF inhibitors that were desymmetrized to afford more drug-like compounds.
- Williams, John D.,Khan, Atiyya R.,Cardinale, Steven C.,Butler, Michelle M.,Bowlin, Terry L.,Peet, Norton P.
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p. 419 - 434
(2014/01/17)
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- A one-pot allylation-hydrostannation sequence with recycling of the intermediate tin waste
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A one-pot allylation and hydrostannation of alkynals where the tin byproduct formed in the first step of the reaction is recycled and used in the second step of the sequence is presented. Specifically, a BF3· OEt2-promoted allylstannation of the aldehyde moiety in the alkynal is followed by the introduction of polymethylhydrosiloxane (PMHS) and catalytic B(C6F5)3, which convert the tin byproduct of the allylation into Bu3SnH, which then hydrostannates the alkyne in the molecule. 119Sn and 11B NMR data suggest an organotin fluoride species is formed during the allylation step and involved in the tin recycling step.
- Ghosh, Banibrata,Amado-Sierra, Maria Del Rosario I.,Holmes, Daniel,Maleczka, Robert E.
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supporting information
p. 2318 - 2321
(2014/05/20)
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- A self-powered polymeric material that responds autonomously and continuously to fleeting stimuli
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Pumped up: Building an autoinductive, self-propagating reaction directly into a polymer has resulted in stimuli-responsive materials that are capable of remembering the presence of a stimulus, even after the stimulus is no longer present. As a proof of co
- Baker, Matthew S.,Yadav, Vinita,Sen, Ayusman,Phillips, Scott T.
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supporting information
p. 10295 - 10299
(2013/10/21)
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- PROCESSES FOR PRODUCING 4-BROMO-2-METHOXYBENZALDEHYDE
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A new synthesis of 4-bromo-2-methoxybenzaldehyde is reported from 1, 4 dibromo 2- fluorobenzene. First, 2-fluoro-4-bromobenzaldehyde is prepared through metal halogen exchange and formylation with a formyl source at 0 °C. After crystallization, this intermediate is reacted with methanol in the presence of potassium carbonate. Subsequently, 4-bromo-2-methoxybenzaldehyde is crystallized.
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Page/Page column 4
(2012/02/02)
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- Highly efficient triarylene conjugated dyes for sensitized solar cells
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A new series of organic dyes containing a triarylamine donor group, a triarylene-linked bridging moiety, and a cyanoacrylic acid acceptor group were synthesized through a simple procedure in high yields. A selected set of substituents were added onto the
- Chang, Yuan Jay,Chow, Tahsin J.
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supporting information; experimental part
p. 9523 - 9531
(2012/05/04)
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- Modulation on C- and N-terminal moieties of a series of potent and selective linear tachykinin NK2 receptor antagonists
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Herein we describe the synthesis of a series of new potent tachykinin NK2 receptor antagonists by the modulation of the Cand N-terminal moieties of ibodutant (MEN 15596, 1). The Nterminal benzo[b]thiophene ring was replaced by different substituted naphthalenes and benzofurans, while further modifications were evaluated at the C-terminal tetrahydropyran moiety. Most compounds demonstrated a high affinity for the human NK2 receptor and high in vitro antagonist potency, indicating that a wide range of substituents at both termini can be incorporated in the molecule without detrimental effects on the interactions with the NK2 receptor. Selected compounds were tested in vivo confirming their activity as NK2 antagonists. In particular, after both iv and id administration to guinea pig, compound 61b was able to antagonize NK2-induced colonic contractions with a potency and duration-of-action fully comparable to the reference compound 1 (MEN 15596, ibodutant).
- Gensini, Martina,Altamura, Maria,Dimoulas, Tula,Fedi, Valentina,Giannotti, Danilo,Giuliani, Sandro,Guidi, Antonio,Harmat, Nicholas J. S.,Meini, Stefania,Nannicini, Rossano,Pasqui, Franco,Tramontana, Manuela,Triolo, Antonio,Maggi, Carlo Alberto
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experimental part
p. 65 - 78
(2010/11/16)
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- 6-SUBSTITUTED PHENOXYCHROMAN CARBOXYLIC ACID DERIVATIVES
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Compounds of Formula (I): in which A1, A2, W, L, G, R7a, R7b, R8, R9 and R10 have the meanings given in the specification, are DP2 receptor modulators useful in the treatment of immunologic diseases.
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Page/Page column 64-65
(2010/01/30)
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- Piperazine Heteroaryl Derivatives as Gpr38 Agonists
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The invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R5, R6, Z, X and B are as defined in the specification. The compounds are partial or full agonists at the GPR38 receptor. Pharmaceutical compositions comprising the compounds, methods of preparing the compounds, uses of the compounds and methods involving the compounds are also provided.
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Page/Page column 16
(2009/01/24)
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- PIPERAZINE HETEROARYL DERIVATES AS GPR38 AGONISTS
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The invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof, (I) wherein R1, R2, R3, R4, R5, R6, Z, X and B are as defined in the specification. The compounds are partial or full agonists at the GPR38 receptor. Pharmaceutical compositions comprising the compounds, methods of preparing the compounds, uses of the compounds and methods involving the compounds are also provided.
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Page/Page column 48
(2010/11/25)
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- Photoinduced C-Br homolysis of 2-bromobenzophenones and Pschorr ring closure of 2-aroylaryl radicals to fluorenones
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(Chemical Equation Presented) A variety of diversely substituted 2-aroylaryl radicals, generated by photoinduced homolysis of 2-bromoarylketones, is shown to undergo Pschorr cyclization to yield fluorenones in moderate to excellent yields. The photochemical results illustrate that the substituents in the two phenyl rings of the 2-bromobenzophenone skeleton exert a dramatic influence on the reactivity of the derived 2-aroylaryl radicals. The disubstitution by methoxy groups in the radical ring renders the aryl σ-radical highly electrophilic and unreactive for hydrogen abstraction and cyclization. On the other hand, the substituents in the non-radical ring that strongly stabilize the hydrofluorenyl π-radical, formed subsequent to the attack of the 2-aroylaryl radical on the non-radical ring, promote cyclization to furnish fluorenones in excellent isolated yields.
- Moorthy, Jarugu Narasimha,Samanta, Subhas
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p. 9786 - 9789
(2008/03/17)
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- CRF RECEPTOR ANTAGONISTS AND METHODS RELATING THERETO
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CRF receptor antagonists are disclosed which may have utility in the treatment of a variety of disorders, including the treatment of disorders manifesting hypersecretion of CRF in mammals, such as stroke. The CRF receptor antagonists of this invention have the following structure (a) including pharmaceutically acceptable salts, esters, solvates, stereoisomers, and prodrugs thereof, wherein R1, R2, R3, Y, Ar, and Het are as defined herein. Compositions containing a CRF receptor antagonist and a pharmaceutically acceptable carrier are also disclosed, as well as methods for use of the same.
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Page/Page column 33-34
(2010/02/12)
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- Halogen-lithium exchange between substituted dihalobenzenes and butyllithium: Application to the regioselective synthesis of functionalized bromobenzaldehydes
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Halogen-lithium interconversion reactions between unsymmetrically substituted mono- and bifunctional dihalobenzenes C6H 3XHal2 and C6H2XYHal2 (Hal=Br, I; X, Y=F, OR, CF3, CH(OMe)2) and butyllithium were investigated. The resultant organolithium intermediates were converted into the corresponding benzaldehydes in moderate to good yields. As a rule, bromine atoms in the position ortho to the functional group were replaced preferentially with lithium. Intramolecular competition experiments with bifunctional systems revealed that fluorine is capable of activating the neighboring bromine atom more strongly than methoxy and dimethoxymethyl groups. On the replacement of the non-activated bromine with iodine a complete reversal of this reactivity pattern can be accomplished due to the preferred iodine-lithium exchange.
- Da?browski, Marek,Kubicka, Joanna,Luliński, Sergiusz,Serwatowski, Janusz
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p. 6590 - 6595
(2007/10/03)
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- ANTIBACTERIAL COMPOUNDS
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A compound of the formula (I), or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof wherein in (I) C is for example formula (D), (E), (H) wherein A and B are independently selected from formulae (i) and (ii) and R2b and R6b, R2b and R6a, R3a and R5a, are for example selected from H, F, OMe and Me; R2b’ and R6b’, R2a’ and R6a’, R3a’, R5a’ are for example selected from H, OMe and Me; R1a and R1b are for example selected from hydroxy, -OSi(tri-(1-6C)alkyl), NR5C(=W) R4, formla (a), formula (b) wherein HET-1 is for example isoxazolyl and HET-2 is for example triazolyl or tetrazolyl. Methods for making compounds of the formula (I), compositions containing them and their use as antibacterial agents are also described.
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- Binding of Phenylalkylamine Derivatives at 5-HT1C and 5-HT2 Serotonin Receptors: Evidence for a Lack of Selectivity
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Certain phenyalkylamine derivatives have been considered to bind selectively at 5-HT2 serotonin receptors.It is now recognized that the most widely used derivatives, i.e., 1-(2,5-dimethoxy-4-X-phenyl)-2-aminopropanes where X = Me (DOM), Br (DOB), and I (DOI) (1-3, respectively) also bind at the more recently identified population of serotonin 5-HT1C receptors.The purpose of the present investigation was to determine whether simple phenylalkylamines bind selectively at one population of receptors over the other.An examination of 34 derivatives reveals (i) similar structure-affinity relationships and (ii) a significant correlation (r = >0.9, n = 25) between 5-HT1C and 5-HT2 affinity.None of the compounds included in the present study displayed more than a 10-fold selectivity for one population of these receptors over the other; the results suggest that these compounds (including the widely used 5-HT2 agonists DOB and DOI) are 5-HT1C/5-HT2 agents.
- Glennon, Richard A.,Raghupathi, Reva,Bartyzel, Piotr,Teitler, Milt,Leonhardt, Sigrun
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p. 734 - 740
(2007/10/02)
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- 5-HT1 and 5-HT2 Binding Characteristics of 1-(2,5-Dimethoxy-4-bromophenyl)-2-aminopropane Analogues
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1-(2,5-Dimethoxy-4-bromophenyl)-2-aminopropane (DOB; 1a) is a purported serotonin (5-HT) agonist that binds selectively to central 5-HT2 binding sites.Systematic removal of any or all of the aromatic substituents had relatively little effect on 5-HT1 binding but reduced 5-HT2 binding by approximately 2 or more orders of magnitude.Demethylation of the 2-methoxy group of 1a, or introduction of N-n-propyl group, doubled 5-HT1-site affinity but decreased 5-HT2-site affinity by 3- and 30-fold, respectively.In tests of stimulus generalization, using rats trained to discriminate DOM from saline, the 2-demethyl and N-propyl derivatives were found to produce stimulus effects similar to those of DOB.In addition, the S-(+) isomer of the iodo analogue of 1a was found to possess one-third the affinity of its R-(-) enantiomer at 5-HT2 sites and also resulted in DOM-stimulus generalization.Of the DOB analogues examined, DOB (1a) possesses optimal selectivity for 5-HT2 binding.
- Glennon, Richard A.,McKenney, J. D.,Lyon, Robert A.,Titeler, Milt
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p. 194 - 199
(2007/10/02)
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