- Synthesis and in vivo evaluation in mice of (123I)-(4- fluorophenyl)(1-(3-iodophenethyl)piperidin-4-yl) methanone as a potential SPECT-tracer for the serotonin 5-HT2A receptor
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This work reports the synthesis, radiolabelling and in vivo evaluation in NMRI mice of [123I]-(4-fluorophenyl)[1-(3-iodophenethyl)piperidin-4- yl]methanone ([123I]-3-I-CO) as a potential SPECT tracer for the 5-HT2A recepto
- Blanckaert,Burvenich,Devos,Slegers
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Read Online
- Method for preparation of aromatic alcohol by photocatalysis of aromatic aldehyde conversion
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The invention relates to a method for preparation of aromatic alcohol by photocatalysis of aromatic aldehyde conversion. By means of a photocatalyst, under the conditions of illumination and inert gas, fatty alcohol is adopted as a proton donor for reduction reaction on aromatic aldehyde to obtain corresponding aromatic alcohol. Fatty alcohol is used as the proton donor, and light energy is used as the energy source to promote high-conversion-rate and high-selectivity synthesis of a series of aromatic alcohol compounds from aromatic aldehyde, the method has universal applicability, and is expected to realize industrial production; and the reaction process is green and environment-friendly, low in cost, easy to operate, short in reaction period, high in conversion rate and good in selectivity.
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Paragraph 0022-0024; 0059-0060
(2020/04/17)
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- Photochemical Homologation for the Preparation of Aliphatic Aldehydes in Flow
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Cheap and readily available aqueous formaldehyde was used as a formylating reagent in a homologation reaction with nonstabilized diazo compounds, enabled by UV photolysis of bench-stable oxadiazolines in a flow photoreactor. Various aliphatic aldehydes were synthesized along with the corresponding derivatized alcohols and benzimidazoles. No transition-metal catalyst or additive was required to affect the reaction, which proceeded at room temperature in 80 min.
- Chen, Yiding,Leonardi, Marco,Dingwall, Paul,Labes, Ricardo,Pasau, Patrick,Blakemore, David C.,Ley, Steven V.
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p. 15558 - 15568
(2019/01/04)
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- Biocatalytic Formal Anti-Markovnikov Hydroamination and Hydration of Aryl Alkenes
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Biocatalytic anti-Markovnikov alkene hydroamination and hydration were achieved based on two concepts involving enzyme cascades: epoxidation-isomerization-amination for hydroamination and epoxidation-isomerization-reduction for hydration. An Escherichia coli strain coexpressing styrene monooxygenase (SMO), styrene oxide isomerase (SOI), ω-transaminase (CvTA), and alanine dehydrogenase (AlaDH) catalyzed the hydroamination of 12 aryl alkenes to give the corresponding valuable terminal amines in high conversion (many ≥86%) and exclusive anti-Markovnikov selectivity (>99:1). Another E. coli strain coexpressing SMO, SOI, and phenylacetaldehyde reductase (PAR) catalyzed the hydration of 12 aryl alkenes to the corresponding useful terminal alcohols in high conversion (many ≥80%) and very high anti-Markovnikov selectivity (>99:1). Importantly, SOI was discovered for stereoselective isomerization of a chiral epoxide to a chiral aldehyde, providing some insights on enzymatic epoxide rearrangement. Harnessing this stereoselective rearrangement, highly enantioselective anti-Markovnikov hydroamination and hydration were demonstrated to convert α-methylstyrene to the corresponding (S)-amine and (S)-alcohol in 84-81% conversion with 97-92% ee, respectively. The biocatalytic anti-Markovnikov hydroamination and hydration of alkenes, utilizing cheap and nontoxic chemicals (O2, NH3, and glucose) and cells, provide an environmentally friendly, highly selective, and high-yielding synthesis of terminal amines and alcohols.
- Wu, Shuke,Liu, Ji,Li, Zhi
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p. 5225 - 5233
(2017/08/17)
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- Antiproliferative activity and SARs of caffeic acid esters with mono-substituted phenylethanols moiety
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A series of CAPE derivatives with mono-substituted phenylethanols moiety were synthesized and evaluated by MTT assay on growth of 4 human cancer cell lines (Hela, DU-145, MCF-7 and ECA-109). The substituent effects on the antiproliferative activity were systematically investigated for the first time. It was found that electron-donating and hydrophobic substituents at 2′-position of phenylethanol moiety could significantly enhance CAPE's antiproliferative activity. 2′-Propoxyl derivative, as a novel caffeic acid ester, exhibited exquisite potency (IC50?=?0.4?±?0.02 & 0.6?±?0.03?μM against Hela and DU-145 respectively).
- Xie, Jin,Yang, Fengzhi,Zhang, Man,Lam, Celine,Qiao, Yixue,Xiao, Jia,Zhang, Dongdong,Ge, Yuxuan,Fu, Lei,Xie, Dongsheng
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p. 131 - 134
(2016/12/27)
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- A General, Practical Triethylborane-Catalyzed Reduction of Carbonyl Functions to Alcohols
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A combination of the abundant and low-cost triethylborane and sodium alkoxide generates a highly efficient catalyst for reduction of esters, as well as ketones and aldehydes, to alcohols using an inexpensive hydrosilane under mild conditions. The catalyst system exhibits excellent chemoselectivity and a high level of functional group tolerance. Mechanistic studies revealed a resting state of sodium triethylalkoxylborate that is the product of the reaction of BEt3 with sodium alkoxide. This borate species reacts with hydrosilane to form NaBEt3H, which rapidly reduces esters.
- Peng, Dongjie,Zhang, Mintao,Huang, Zheng
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supporting information
p. 14737 - 14741
(2015/10/19)
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- HETEROCYCLIC MODULATORS OF HIF ACTIVITY FOR TREATMENT OF DISEASE
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The present invention relates to compounds and methods which may be useful as inhibitors of HIF pathway activity for the treatment or prevention of cancer and other hypoxia-mediated diseases.
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Paragraph 0356-0357
(2014/03/24)
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- A Phosphine-Catalyzed Novel Asymmetric [3+2] Cycloaddition of C,N-Cyclic Azomethine Imines with δ-Substituted Allenoates
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Catalytic asymmetric [3+2] cycloadditions of C,N-cyclic azomethine imines with δ-substituted allenoates have been developed in the presence of (S)-Me-f-KetalPhos, affording functionalized tetrahydroquinoline frameworks in good yields with high diastereo- and good enantioselectivities under mild condition. The substrate scope has been also examined. This is the first time that δ-substituted allenoates have been applied as a δ,γ-C-C bond participated C 2 synthon in asymmetric synthesis. Another round: Catalytic asymmetric [3+2] cycloaddition of C,N-cyclic azomethine imines with δ-substituted allenoates have been developed in the presence of (S)-Me-f-KetalPhos, affording functionalized tetrahydroquinoline frameworks in good yields with high diastereo- and good enantioselectivities under mild conditions. This is the first example applying δ-substituted allenoates as C 2 synthons in asymmetric δ,γ-C-C bond formation.
- Wang, De,Lei, Yu,Wei, Yin,Shi, Min
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supporting information
p. 15325 - 15329
(2016/02/18)
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- Copper-catalyzed enantioselective additions to oxocarbenium ions: Alkynylation of isochroman acetals
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We have developed an enantioselective, copper(I)-catalyzed addition of terminal alkynes to racemic isochroman acetals. This method is one of the first transition-metal-catalyzed approaches to enantioselective additions to prochiral oxocarbenium ions. In this reaction, TMSOTf is used to form the oxocarbenium ion in situ under conditions compatible with simultaneous formation of the chiral copper acetylide. By using a bis(oxazoline) ligand, good yields and enantioselectivities are observed for a variety of enantioenriched 1-alkynyl isochromans.
- Maity, Prantik,Srinivas, Harathi D.,Watson, Mary P.
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supporting information; experimental part
p. 17142 - 17145
(2011/12/13)
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- Practical and chemoselective reduction of acyl chloride to alcohol by borohydride in aqueous dichloromethane
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A simple methodology for the reduction of acid chlorides to their corresponding alcohols has been developed. Various carboxylic acids were converted to alcohols in excellent yields using NaBH4-K2CO3 in a mixed solvent system of dichloromethane and water (1:1) in the presence of a phase-transfer catalyst at low temperature. The importance of the work is its simplicity, selectivity, excellent yield, and very short reaction time. This new reduction condition has proved to be an excellent chemoselective method for a range of acid chlorides in the presence of various functional groups.
- Rajan, Ramya,Badgujar, Sachin,Kaur, Kamaljit,Malpani, Yashwardhan,Kanjilal, Pranab R.
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experimental part
p. 2897 - 2907
(2010/11/18)
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- Catalytic enantioselective 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines with α,β-unsaturated aldehydes
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(Figure Presented) A yet-unexploited class of azomethine imines, C,N-cyclic azomethine imines, could be successfully employed in highly enantioselective 1,3-dipolar cycloaddition with enals catalyzed by titanium-BINOLate to give pharmaceutically attractive tetrahydroisoquinoline and piperidine motifs. Copyright
- Hashimoto, Takuya,Maeda, Yuko,Omote, Masato,Nakatsu, Hiroki,Maruoka, Keiji
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supporting information; experimental part
p. 4076 - 4077
(2010/05/15)
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- 2-(HETERO-)ARYL,4-CARBONYL SUBSTITUTED PYRAZOLE DERIVATIVES AS INHIBITORS OF P38 MITOGEN-ACTIVATED PROTEIN KINASE
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Compounds of formula (I) are inhibitors of p38 MAP kinase activity, and are useful in the treatment of, inter alia, inflammatory and autoimmune disease wherein Ring A is aryl, heteroaryl or heterocyclyl of 5-13 atoms; Ring B is optionally substituted aryl or heteroaryl of 5-13 atoms; Z is (a) a radical of formula -(CH2)z-X1-L1-Y- NHCHR1R2 or (b) a radical of formula -(CH2)z-Y1-L1-R wherein R1R2CHNH- and R are respectively N- and C-linked amino acid or amino acid ester groups as defined in the description, and -Y-L1-X1-(CH2)z- and -L1-Y1-(CH2)z- are linker radicals as defined in the description; R7 is hydrogen or -C(=O)R' where R' is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl or (C1-C6)haloalkyl; R8 is hydrogen or (C1C6)alkyl; R9 is hydrogen, halogen, hydroxyl, (C1-C6)alkoxy, (C1-C6)alkyl; R18 is hydrogen, halogen, hydroxyl, (C1C6)alkoxy (C1-C6)alkyl, - NRaRb where Ra and Rb are hydrogen or (C1-C6)alkyl, or optionally substituted aryl, heteroaryl or heterocyclyl or Ra and Rb when taken together with the nitrogen to which they are attached form a cyclic amino group of up to 6 ring atoms; R19 is hydrogen, halogen, (C1C6)alkoxy, or (C1C6)alkyl.
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Page/Page column 38
(2008/12/05)
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- Novel aminoethylbiphenyls as 5-HT7 receptor ligands
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The synthesis of a series of aminoethylbiphenyls as novel 5-HT7 receptor ligands is described. The novel derivatives exhibit high affinity for the 5-HT7 receptor with selectivity toward 5-HT1A receptor.
- Paillet-Loilier, Magalie,Fabis, Frederic,Lepailleur, Alban,Bureau, Ronan,Butt-Gueulle, Sabrina,Dauphin, Francois,Lesnard, Aurelien,Delarue, Catherine,Vaudry, Hubert,Rault, Sylvain
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p. 3018 - 3022
(2008/02/07)
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- NEW OXABISPIDINE COMPOUNDS FOR THE TREATMENT OF CARDIAC ARRHYTHMIAS
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There is provided compounds of formula I, [Chemical formula should be inserted here. Please see paper copy] wherein R1 to R4 , R41 to R46 and Z have meanings given in the description, which are useful in the prophylaxis and in the treatment of arrhythmias, in particular atrial and ventricular arrhythmias
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Page/Page column 89
(2010/11/27)
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- Discovery of S-[5-amino-1-(4-fluorophenyl)-1H-pyrazol-4-yl]-[3-(2,3- dihydroxypropoxy)phenyl]-methanone (RO3201195), an orally bioavailable and highly selective inhibitor of p38 Map kinase
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A novel class of highly selective inhibitors of p38 MAP kinase was discovered from high throughput screening. The synthesis and optimization of a series of 5-amino-N-phenyl-1H-pyrazol-4-yl-3-phenylmethanones is described. An X-ray crystal structure of this series bound in the ATP binding pocket of unphosphorylated p38a established the presence of a unique hydrogen bond between the exocyclic amine of the inhibitor and threonine 106 which likely contributes to the selectivity for p38. The crystallographic information was used to optimize the potency and physicochemical properties of the series. The incorporation of the 2,3-dihydroxypropoxy moiety on the pyrazole scaffold resulted in a compound with excellent drug-like properties including high oral bioavailability. These efforts identified 63 (RO3201195) as an orally bioavailable and highly selective inhibitor of p38 which was selected for advancement into Phase I clinical trials.
- Goldstein, David M.,Alfredson, Tom,Bertrand, Jay,Browner, Michelle F.,Clifford, Ken,Dalrymple, Stacie A.,Dunn, James,Freire-Moar, Jose,Harris, Seth,Labadie, Sharada S.,La Fargue, JoAnn,Lapierre, Jean Marc,Larrabee, Susan,Li, Fujun,Papp, Eva,McWeeney, Daniel,Ramesha, Chakk,Roberts, Rick,Rotstein, David,San Pablo, Bong,Sjogren, Eric B.,So, On-Yee,Talamas, Francisco X.,Tao, Will,Trejo, Alejandra,Villasenor, Armando,Welch, Mary,Welch, Teresa,Weller, Paul,Whiteley, Phyllis E.,Young, Kelly,Zipfel, Sheila
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p. 1562 - 1575
(2007/10/03)
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- THIAZOLE DERIVATIVES HAVING VAP-1 INHIBITORY ACTIVITY
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A compound of the formula (I), (II), (III) or (IV): wherein each symbol is as defined in the specification,or a pharmaceutically acceptable salt thereof useful as a vascular adhesion protein-1 (VAP-1) inhibitor, a pharmaceutical composition, a method for preventing or treating a VAP-1 associated disease, especially macular edema, which method includes administering an effective amount of the compound or a pharmaceutically acceptable salt thereof to a subject, and the like.
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Page/Page column 67-68
(2008/06/13)
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- THIAZOLE DERIVATIVES AND THEIR USE AS VAP-1 INHIBITORS
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A compound of the formula (I): R1-NH-X-Y-Z (I) wherein R1 is acyl; X is a bivalent residue derived from optionally substituted thiazole; Y is a bond, lower alkylene or -COHN-; and Z is a groupe of the formulae (II) or (III) wherein R
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Page 228-229
(2010/02/07)
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- Aminoisoquinolines and aminotheinopyridine derivatives and their use as anti-inflammatory agents
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PCT No. PCT/SE97/00589 Sec. 371 Date Aug. 19, 1997 Sec. 102(e) Date Aug. 19, 1997 PCT Filed Apr. 9, 1997 PCT Pub. No. WO97/38977 PCT Pub. Date Oct. 23, 1997Compounds of formula I wherein R, R1, R2, and R3 and A are as defined herein, together with pharmaceutically acceptable salts, enantiomers or tautomers are useful as pharmaceuticals, particularly in the treatment of inflammatory disease.
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- 2-substituted (2SR)-2-amino-2-((1SR,2SR)-2-carboxycycloprop-1- yl)glycines as potent and selective antagonists of group II metabotropic glutamate receptors. 2. Effects of aromatic substitution, pharmacological characterization, and bioavailability
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In this paper we describe the synthesis of a series of α-substituted analogues of the potent and selective group II metabotropic glutamate receptor (mGluR) agonist (1S,1'S,2'S)-carboxycyclopropylglycine (2, L-CCG 1). Incorporation of a substituent on the amino acid carbon converted the agonist 2 into an antagonist. All of the compounds were prepared and tested as a series of four isomers, i.e., two racemic diastereomers. On the basis of the improvement in affinity realized for the α-phenylethyl analogue 3, in this paper we explored the effects of substitution on the aromatic ring as a strategy to increase the affinity of these compounds for group II mGluRs. Affinity for group II mGluRs was measured using [3H]glutamic acid (Glu) binding in rat forebrain membranes. Antagonist activity was confirmed for these compounds by measuring their ability to antagonize (1S,3R)-1- aminocyclopentane-1,3-dicarboxylic acid-induced inhibition of forskolin stimulated cyclic-AMP in RGT cells transfected with human mGluR2 and mGluR3. Meta substitution on the aromatic ring of 3 with a variety of substituents, both electron donating (e.g., methyl, hydroxy, amino, methoxy, phenyl, phenoxy) and electron withdrawing (e.g., fluorine, chlorine, bromine, carboxy, trifluoromethyl) gave from 1.5- to 4.5-fold increases in affinity. Substitution with p-fluorine, as in 97 (IC50 = 0.022 ± 0.002), was the exception. Here, a greater increase in affinity was realized than for either the ortho- or meta-substituted analogues; 97 was the most potent compound resulting from monosubstitution of the aromatic. At best, only modest increases in affinity were realized for certain compounds bearing either two chlorines or two fluorines, and two methoxy groups gave no improvement in affinity (all examined in a variety of substitution patterns). Three amino acids, 4, 5, and 104, were resolved into their four constituent isomers, and affinity and functional activity for group II mGluRs was found to reside solely in the S,S,S-isomers of each, consistent with 1. With an IC50 = 2.9 ± 0.6 nM, the resolved xanthylmethyl compound 168 was the most potent compound from this SAR. Amino acid 168 demonstrated high plasma levels following intraperitoneal (ip) administration and readily penetrated into the brain. This compound, however, had only limited (~5%) oral bioavailability. Systemic administration of 168 protected mice from limbic seizures produced by the mGluR agonist 3,5-dihydroxyphenylglycine, with an ED50 = 31 mg/kg (ip, 60 min preinjection). Thus, 168 represents a valuable tool to study the role of group II mGluRs in disease.
- Ornstein, Paul L.,Bleisch, Thomas J.,Arnold, M. Brian,Kennedy, Joseph H.,Wright, Rebecca A.,Johnson, Bryan G.,Tizzano, Joseph P.,Helton, David R.,Kallman, Mary Jeanne,Schoepp, Darryle D.,Hérin, Marc
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p. 358 - 378
(2007/10/03)
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- Prostaglandin analogs
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Thromboxane receptor antagonist activity is exhibited by compounds of the formula STR1 wherein: V is --(CH 2) m --, --O--, or STR2 but if V is --O--or STR3 R 3 and R 4 must complete an aromatic ring; W is --(CH 2) 2 --, --CH CH-- or phenylene;X is a single bond, --CH CH--, --(CH 2) n --, or --O--(CH 2) n --; or X is branched alkylene or --O--branched alkylene wherein W is linked to Y through a chain n carbon atoms long;Y is --CO 2 H, --CO 2 alkyl, --CO 2 alkali metal, --CH 2 OH, --CONHSO 2 R 5, --CONHR 6, or --CH 2 -5-tetrazolyl;Z is O or NH;R 3 and R 4 are each independently hydrogen or alkyl or R 3 and R 4 together complete a ring optionally substituted through a ring carbon with a halo, lower alkyl, phenyl, halo (lower alkyl), halophenyl, oxo or hydroxyl group; and the remaining symbols are as defined in the specification.
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- Alpha-aryl-alpha-phenylethyl-1H-1,2,4-triazole-1-propanenitriles
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This invention relates to substituted and unsubstituted alpha-aryl-alpha-phenylethyl-1H-1,2,4-triazole-1-propanenitriles, their enantiomorphs, acid addition salts and metal salt complexes. These compounds, enantiomorphs, salts and complexes are highly act
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- Interphenylene 7-oxabicyclo[2.2.1]heptane thromboxane A2 antagonists. Semicarbazone ω-chains
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A series of chiral interphenylene 7-oxabicyclo[2.2.1]heptane semicarbazones 19-26 were prepared and evaluated for their in vitro thromboxane (TxA2) antagonistic activity and in vivo duration of action. The potency of 19-26 was found to be highly dependent on the substitution pattern of the interphenylene ring and decreased in the order ortho > meta >> para. SQ 35,091 (25), [1S-(1α,2α,3α,4α)]-2-[[3-[[[(phenylamino)carbonyl]hydrazono] methyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, was identified as a potent and long-acting TxA2 antagonist. In human platelet rich plasma SQ 35,091 inhibited arachidonic acid (800 μM) and U-46,619 (10 μM) induced aggregation with I50 values of 3 and 12 nM, respectively. In contrast, no inhibition of ADP (20 μM) induced aggregation was observed at >1000 μM. Receptor binding studies with [3H]-SQ 29,548 showed SQ 35,091 was a competitive antagonist with a K(d) value of 1.0 ± 0.1 nM in human platelet membranes. In vivo SQ 35,091 (0.2 mg/kg po) showed extended protection (T50 = 16 h) from U-46,619 (2 mg/kg iv) induced death in mice. These compounds have for the first time demonstrated that a metabolically stable interphenylene α-sidechain can be introduced into a prostanoid-like series of TxA2 antagonists with the maintenance of potent antagonistic activity.
- Misra,Brown,Han,Harris,Hedberg,Webb,Hall
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p. 2882 - 2891
(2007/10/02)
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