- Potent and selective indolomorphinan antagonists of the kappa-opioid receptor
-
The indole moiety in the delta-opioid antagonist, naltrindole (2, NTI), was employed as a scaffold to hold an 'address' for interaction with the kappa-opioid receptor. The attachment of the address to the 5'-position of the indole moiety was based on superposition of NTI upon the kappa antagonist, norbinaltorphimine (1, norBNI). A variety of cationic groups were employed as a kappa address in an effort to investigate its interaction with the anionic address subsite, Glu297, on the kappa receptor. Some of the groups that were employed for this purpose were amines, amidines, guanidines, and quaternary ammonium. Members of the series were found to have a varying degree of kappa antagonist potency and kappa selectivity when tested in smooth muscle preparations. The 5'-guanidine derivative 12a (GNTI) was the most potent member of the series and had the highest kappa selectivity ratio. GNTI was 2 times more potent and 6-10-fold more selective than norBNI (1). In general, the order of potency in the series was: guanidines amines. The kappa antagonist potency appeared to be a function of a combination of the pK(a) and distance constraint of the cationic substituent of the ligand. Receptor binding studies were qualitatively in agreement with the pharmacological data. Molecular modeling studies on 12a suggested that the protonated N-17 and guanidinium groups of GNTI are associated with Asp138 (TM3) and Glu297 (TM6), respectively, while the phenolic hydroxyl may be involved in donor - acceptor interactions with the imidazole ring of His291. It was concluded that the basis for the high kappa selectivity of GNTI is related both to association with the nonconserved Glu297 residue and to unfavorable interactions with an equivalent position in mu- and delta-opioid receptors.
- Stevens Jr., William C.,Jones, Robert M.,Subramanian, Govindan,Metzger, Thomas G.,Ferguson, David M.,Portoghese, Philip S.
-
-
Read Online
- Ionizable isotopic labeling reagent for relative quantification of amine metabolites by mass spectrometry
-
A powerful approach to relative quantification by mass spectrometry is to employ labeling reagents that target specific functional groups in molecules of interest. A quantitative comparison of two or more samples may be readily accomplished by using a chemically identical but isotopically distinct labeling reagent for each sample. The samples may then be combined, subjected to purification steps, and mass analyzed. Comparison of the signal intensities obtained from the isotopically labeled variants of the target analyte(s) provides quantitative information on their relative concentrations in the sample. In this report, we describe the synthesis and use of heavy and light isotopic forms of methyl acetimidate for the relative quantification of amine-containing species. The principal advantages of methyl acetimidate as a labeling reagent are that the reaction product is positively charged and hydrophobicity is increased, both of which enhance electrospray ionization efficiency and increase detection sensitivity. The quantitative nature of the analysis was demonstrated in model metabolomics experiments in which heavy and light labeled Arabidopsis extracts were combined in different ratios. Finally, the labeling strategy was employed to determine differences in the amounts of amine-containing metabolites for Arabidopsis seeds germinated under two different conditions.
- Shortreed, Michael R.,Lamos, Shane M.,Frey, Brian L.,Phillips, Margaret F.,Patel, Madhusudan,Belshaw, Peter J.,Smith, Lloyd M.
-
-
Read Online
- Preparation method of cefathiamidine hydrochloride
-
The invention provides a preparation method of cefathiamidine hydrochloride. In particular, by adopting a reverse dropwise adding manner, the intermediate product vinylidene chloride is added dropwise to the ammonia methanol to generate stable cefathiamidine, and the reverse dripping mode not only effectively inhibits the decomposition of the aramidine, but also the yield of cefathiamidine hydrochloride can reach 95% or above. The method is safe to operate. The method is high in yield and low in energy consumption, and is very suitable for large-scale application.
- -
-
Paragraph 0047; 0062; 0064; 0065; 0068; 0070; 0071; ...
(2021/09/01)
-
- A hydrogen chloride producing toluene diisocyanate methyl-acetate production method
-
The invention discloses a method for producing trimethyl orthoacetate by utilizing hydrogen chloride (HCl) generated during production of toluene diisocynate (TDI). The method comprises the following steps: carrying out pressure boosting on a dried normal-pressure and low-temperature HCl waste gas taken as a byproduct during production of TDI and then feeding methyl alcohol into HCl so as to prepare an alcohol acid; carrying out a salt forming reaction on the alcohol acid and acetonitrile in an inert solvent so as to prepare an ethyleneimine methyl ether hydrochloride; feeding methyl alcohol twice, carrying out an alcoholysis reaction and distilling so as to prepare trimethyl orthoacetate. According to the method, dried normal-pressure and low-temperature HCl generated during the production of TDI is taken a raw material, namely, the recycling of a waste material is realized, so that the cost is lowered; the safety and the environmental friendliness are realized. The alcohol acid is prepared, so that the problems that the metering of HCl is inaccurate and the temperature is difficult to control because a large quantity of heat is released during the salt forming reaction are solved; the solvent with a high boiling point is used, so that the safe and environment-friendly problem that the solvent with a low boiling point is toxic and flammable is solved; the continuous rectification is carried out, so that the problem of long production cycle is solved. The yield of prepared trimethyl orthoacetate can reach 76% to 80%.
- -
-
Paragraph 0035-0046
(2017/02/24)
-
- METHOD FOR PREPARATION OF BENZIMIDAZOLE DERIVATIVES
-
The present invention provides a method for preparing a compound with a benzimidazole structure with an excellent yield using a low-cost starting material, not requiring an additional separation process, or not using a dangerous reagent during the manufacturing process. Furthermore, the present invention also provides an intermediate and a final product produced by the preparing method.
- -
-
Paragraph 138; 139; 140
(2015/02/02)
-
- Iridium-catalyzed hydrogenation of β-dehydroamino acid derivatives using monodentate phosphoramidites
-
The iridium-catalyzed asymmetric hydrogenation of 13 different β-dehydroamino acid derivatives to give optically active β-amino acid esters has been examined. Readily accessible monodentate octahydrobinaphthol- based phosphoramidites were used as chiral ligands. Good to excellent enantioselectivities and yields were obtained for the E isomers, whereas poorer catalyst performance was found for the Z isomers. Importantly, to obtain high enantioselectivity, substitution at the 3,3′-positions of the ligands was necessary. Enantioselectivities of up to 94% ee were achieved under optimized conditions. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Enthaler, Stephan,Erre, Giulia,Junge, Kathrin,Schroeder, Kristin,Addis, Daniele,Michalik, Dirk,Hapke, Marko,Redkin, Dmitry,Beller, Matthias
-
experimental part
p. 3352 - 3362
(2009/04/07)
-
- METHOD FOR PRODUCING IMIDE ETHER COMPOUND
-
A method for producing an imide ether compound in high yield is provided. The method is characterized in that a nitrile compound, an alcohol and a hydrogen halide are continuously introduced into a flow reaction apparatus comprising a mixing vessel and a flow reactor, to react them with one another. Since the reaction proceeds with 1 : 1 by the use of a flow reactor, an improved selectivity is achieved and the formation of a by-product is reduced, which results in the efficient production of an imide ether compound.
- -
-
-
- METHOD FOR PRODUCING IMIDE ETHER COMPOUND
-
A method for producing an imide ether compound in high yield is provided. The method is characterized in that a nitrile compound, an alcohol and a hydrogen halide are continuously introduced into a flow reaction apparatus comprising a mixing vessel and a flow reactor, to react them with one another. Since the reaction proceeds with 1 : 1 by the use of a flow reactor, an improved selectivity is achieved and the formation of a by-product is reduced, which results in the efficient production of an imide ether compound.
- -
-
Page/Page column 18-23; 28; 1/4; 3/4-4/4
(2008/06/13)
-
- Preparation and resolution of a modular class of axially chiral quinazoline-containing ligands and their application in asymmetric rhodium-catalyzed olefin hydroboration
-
The preparation and resolution of a series of axially chiral quinazoline-containing ligands is described in which the key steps are the metal-catalyzed naphthyl-phosphorus bond formation, the naphthalene-quinazoline Suzuki coupling, and the preparation of the Suzuki electrophilic components from the corresponding imidate and anthranilic acid. Diastereomeric palladacycles derived from the racemic phosphinamines and (+)-di-μ-chlorobis[(R)- dimethyl(1-(1-naphthyl)ethyl)-aminato-C2,N]dipalladium(II) were separated by fractional crystallization. The configuration of the resulting diastereomers was determined by X-ray crystallographic analysis. Displacement of the resolving agent by reaction with 1,2-bis(diphenylphosphino)ethane afforded enantiopure ligand in each case. Their rhodium complexes were prepared and applied in the enantioselective hydroboration of a range of vinylarenes. The quinazolinap catalysts were found to be extremely active, giving excellent conversions, good to complete regioselectivities, and the highest enantioselectivities obtained to date for several members of the vinylarene class, including cis-β-methylstyrene (97%), cis-stilbene (99%), and indene (99.5%).
- Connolly, David J.,Lacey, Patrick M.,McCarthy, Mary,Saunders, Cormac P.,Carroll, Anne-Marie,Goddard, Richard,Guiry, Patrick J.
-
p. 6572 - 6589
(2007/10/03)
-
- A facile and versatile route to 2-substituted-4(3H)-quinazolinones and quinazolines
-
A range of 2-aryl and 2-alkyl quinazolinones have been prepared in moderate to good yields from the reaction of anthranilic acid and the appropriately substituted imidate in a facile, mild, onepot procedure. Subsequent reaction with phosphorus oxychloride afforded the corresponding 4-chloro-2-substituted quinazolines, which are useful synthetic intermediates, in good to high yields. Product isolation was facilitated by the development of work up procedures for both reactions that did not include purification by column chromatography.
- Connolly,Guiry
-
p. 1707 - 1710
(2007/10/03)
-
- 2-β-D-RIBOFURANOSYLBENZOXAZOLE FROM 2,5-ANHYDRO-D-ALLONOIMIDATE, AND 1,3-DIMETHYL-8-β-D-RIBOFURANOSYLXANTHINE FROM 2,5-ANHYDRO-D-ALLONO-THIOIMIDATES AND -DITHIOATES
-
The ability of imidates, thioimidates, and dithioates to react with o-aminophenol (2) and 5,6-diamino-1,3-dimethyluracil (6) was studied, using nonsaccharide model compounds, as well as saccharide derivatives.All of the model compounds gave 2-methylbenzoxazole, but only ethyl dithioacetate gave a purine derivative with 6.Methyl 2,5-anhydro-D-allonoimidate hydrochloride reacted with 2 to yield 2-β-D-ribofuranosylbenzoxazole, but failed to react with compound 6.On reaction with compound 6 such fully acylated thioimidates as ethyl and benzyl 2,5-anhydrotri-O-benzoyl- or tri-O-p-toluoyl-D-allonothioimidate hydrochloride yielded amidines that underwent aromatization of the furanose ring.Such monoacylated thioimidates as ethyl or benzyl 2,5-anhydro-6-O-benzoyl-D-allonothioimidate hydrochloride yielded, with compound 6, 8-(5-O-benzoyl-β-D-ribofuranosyl)-1,3-dimethylxanthine, without aromatization.Such dithioates as benzyl 2,5-anhydro-6-O-benzoyl-D-allonodithioate and ethyl 2,5-anhydrotri-O-benzoyl-D-allonodithioate were obtained by treating the corresponding thioimidate with H2S in pyridine.With compound 6, the first yielded 8-(5-O-benzoyl-β-D-ribofuranosyl)-1,3-dimethylxanthine, which afforded the free C-nucleoside 1,3-dimethyl-8-β-D-ribofuranosylxanthine on treatment with methanolic ammonia.
- Khadem, Hassan S. El,Kawai, Joshua
-
p. 271 - 284
(2007/10/02)
-
- Synthesis and Structure of Alkyl N-Acylimidates
-
Alkyl N-acylimidates 1 are prepared more easily and in higher yields than before by reaction of alkyl imidate hydrochlorides 5 with acyl halides 7 in the presence of 2.2 mol of base (14 examples).The X-ray analysis of a crystalline derivative (1dbd) shows, that the C=N- and C=O parts are twisted significantly (torsional angle 77.6 deg).The stereochemical, dynamic and electronic properties of the compounds 1 are interpreted by means of ab initio 3-21 G calculations on conformers of the parent system HO-CH=N-CH=O (8).Low rotational (ca. 6 kcal/mol) and inversional (max. 8 kcal/mol) barriers indicate the many favourable electronic interactions between the C=N- and the C=O groups in such N-functionalised imine derivatives.The compound 1 are significantly higher in energy than bisacylamines and are therefore suggested to be superior, more reactive synthetic C-N-C building blocks.The spectroscopic properties (IR, 13C- and 1H NMR, MS) are given and discussed.
- Kupfer, Rainer,Nagel, Michael,Wuerthwein, Ernst-Ulrich,Allmann, Rudolf
-
p. 3089 - 3104
(2007/10/02)
-
