79-22-1

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Found in biomolecules, pharmaceuticals, and agrochemicals, amide-containing molecules are ubiquitous in nature, and their derivatization represents a significant methodological goal in fluorine chemistry. Trifluoromethyl amides have emerged as important functional groups frequently found in pharmaceutical compounds. To date, there is no strategy for synthesizing N-trifluoromethyl amides from abundant organic carboxylic acid derivatives, which are ideal starting materials in amide synthesis. Here, we report the synthesis of N-trifluoromethyl amides from carboxylic acid halides and esters under mild conditions via isothiocyanates in the presence of silver fluoride at room temperature. Through this strategy, isothiocyanates are desulfurized with AgF, and then the formed derivative is acylated to afford N-trifluoromethyl amides, including previously inaccessible structures. This method shows broad scope, provides a platform for rapidly generating N-trifluoromethyl amides by virtue of the diversity and availability of both reaction partners, and should find application in the modification of advanced intermediates.

The photolytic activation of palladium(II) and platinum(II) complexes [M(BPI)(R)] (R = alkyl, aryl) featuring the 1,3-bis(2-pyridylimino)isoindole (BPI) ligand has been investigated in various solvents. In the absence of oxygen, the formation of chloro complexes [M(BPI)Cl] is observed in chlorinated solvents, most likely due to the photolytic degradation of the solvent and formation of HCl. The reactivity of the complexes toward oxygen has been studied both experimentally and computationally. Excitation by UV irradiation (365 nm) of the metal complexes [Pt(BPI)Me] and [Pd(BPI)Me] leads to distortion of the square-planar coordination geometry in the excited triplet state and a change in the electronic structure of the complexes that allows the interaction with oxygen. TD-DFT computational studies suggest that, in the case of palladium, the Pd(III) superoxide intermediate [Pd(BPI)(κ1-O2)Me] is formed and, in the case of platinum, the Pt(IV) peroxide intermediate [Pt(BPI)(κ2-O2)Me]. For alkyl complexes where metal-carbon bonds are sufficiently weak, the photoactivation leads to the insertion of oxygen into the metal-carbon bond to generate alkylperoxo complexes: for example [Pd(BPI)OOMe], which has been isolated and structurally characterized. For stronger M-C(aryl) bonds, the reaction of [Pt(BPI)Ph] with O2 and light results in a Pt(IV) complex, tentatively assigned as the peroxo complex [Pt(BPI)(κ2-O2)Ph], which in chlorinated solvents reacts further to give [Pt(BPI)Cl2Ph], which has been isolated and characterized by scXRD. In addition to the facilitation of oxygen insertion reactions, UV irradiation can also affect the reactivity of other components in the reaction mixture, such as the solvent or other reaction products, which can result in further reactions. Labeling studies using [Pt(BPI)(CD3)] in chloroform have shown that photolytic reactions with oxygen involve degradation of the solvent.

Chloroformates are key reagents for synthesizing carbonates and carbamates. The present study reports a novel photo-on-demand in situ synthesis of chloroformates with a CHCl3 solution containing a primary alkyl alcohol. It further allowed the one-pot synthesis of carbonates and carbamates through subsequent addition of alcohols or amines, respectively.

A series of 3-amino-5-benzylphenol derivatives were designed and synthesized. Among them, (3-benzyl-5-hydroxyphenyl)carbamates were found to exert good inhibitory activity against M. tuberculosis H37Ra, H37Rv and clinically isolated multidrug-resistant M. tuberculosis strains (MIC = 0.625-6.25 μg/mL). The privileged compounds 3i and 3l showed moderate cytotoxicity against cell line A549. Compound 3l also exhibited potent in vivo inhibitory activity on a mouse infection model via the oral administration. The results demonstrated 3-hydroxyphenylcarbamates as a class of new antitubercular agents with good potential.

The invention provides hepatitis C virus inhibitors, and pharmaceutical compositions and an application thereof, wherein the hepatitis C virus inhibitors are compounds represented by the formula (I), or crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof. The compounds have better inhibitory activity of a hepatitis C virus protein NS5A, have better pharmacodynamic/pharmacokinetic properties, have good applicability and high safety, can be used for preparing drugs for treatment of hepatitis C virus infection, and have good prospects for market development.

Dissolved hexachlororuthenate(IV) effectively catalyzes the photodecomposition of chloroform to hydrogen chloride and phosgene under near-UV (λ > 345 nm) irradiation, whereby RuCl62- is not itself photocatalytically active, but is photochemically transformed into a species that is active, possibly RuCl5(CHCl3)-. Conversion to a photoactive species during irradiation is consistent with the acceleration of the decomposition rate during the early stages and with the apparent inverse dependence of the decomposition rate on the initial concentration of RuCl62-. The displacement of Cl - by CHCl3 in the coordination sphere to create the photoactive species is consistent with the retardation of photodecomposition by both Cl- and H2O. The much smaller photodecomposition rate in CDCl3 suggests that C-H bond dissociation occurs during the primary photochemical event, which is also consistent with the presence of a CHCl3 molecule in the first coordination sphere. In the presence of RuCl62-, chloroform decomposes under near-UV irradiation to phosgene and hydrogen chloride. The photoactive species is suggested to be RuCl5(CHCl3) -.

We report a series of irreversible transglutaminase 2 inhibitors starting from a known lysine dipeptide bearing an acrylamide warhead. We established new SARs resulting in compounds demonstrating improved potency and better physical and calculated properties. Transglutaminase selectivity profiling and in vitro ADME properties of selected compounds are also reported.

A carbonic acid ester is provided that is represented by the formula below and has a melting point of no greater than 0° C. (In the formula, R1 and R2 independently denote a saturated hydrocarbon group, R1 is a branched chain, and R2 is a straight or branched chain). There is also provided a magnetic recording medium that includes a non-magnetic support and, above the support, at least one magnetic layer including a ferromagnetic powder dispersed in a binder, the magnetic layer including the carbonic acid ester. Furthermore, there is provided a magnetic recording medium including a support and, above the support, a non-magnetic layer including a non-magnetic powder dispersed in a binder, and above the non-magnetic layer, at least one magnetic layer including a ferromagnetic powder dispersed in a binder, the non-magnetic layer and/or the magnetic layer including the carbonic acid ester.

Novel fenicol compounds having useful properties as antibiotic prodrugs, are provided, together with methods of making and using these new compounds.

A series of polysubstituted and fused heterocycle derivatives of acylthiourea was prepared and the biological activity against influenza virus was evaluated. Of the analogues that demonstrated IC50s 0.1 μM, acylthiourea derivatives 16 and 50 were further investigated as candidates with the most potential for future development. The SAR of these compounds are discussed and they represent a novel class of highly potent and selective inhibitors of influenza virus.

A series of substituted acyl(thio)urea and 2H-1,2,4-thiadiazolo [2,3-a] pyrimidine derivatives were prepared and both of their cell culture and enzymatic activity toward influenza virus were tested. Their in vitro neuraminidase inhibitory activities were in good agreement with the corresponding activities in cultured cells and they were evaluated as potent neuraminidase inhibitors. Of the analogues that demonstrated IC50s 0.1 μM, 16 and 60 were further investigated as candidates with the most potential for future development. The molecular docking work of the representative compound was described to provide more insight into their mechanism of action and further rationalize the observations of this new series herein, which represents a novel class of highly potent and selective inhibitors of influenza virus.

The products of the gas-phase elimination of methyl oxalyl chloride are methyl chloroformate and carbon monoxide. The kinetics were determined in a static system over the temperature range 280.3-320.7°C and pressure range 56-140.4 Torr. The reaction, in vessels seasoned with allyl bromide and in the presence of the free-radical inhibitor cyclohexene, is homogeneous, unimolecular and follows a first-order rate law. The rate coefficients are given by the Arrhenius equation: log[k1(s-1)] = (12.73 ± 0.58)-(174.3±6.3) kJ mol-1 (2.303 RT)-1. Theoretical studies of the mechanism at the semi-empirical PM3 and MP2/6-31G* levels imply a concerted non-synchronous process. Analysis of the three-membered ring transition state suggests that polarization of the Cl-C(=O) bond is rate limiting in the elimination process. The kinetics and thermodynamic parameters are in good agreement with the experimental values.

This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as alpha 1a adrenergic receptor antagonists. One application of these compounds is in the treatment of benign prostatic hyperplasia. These compounds are selective in their ability to relax smooth muscle tissue enriched in the alpha 1a receptor subtype without at the same time inducing hypotension. One such tissue is found surrounding the urethral lining. Therefore, one utility of the instant compounds is to provide acute relief to males suffering from benign prostatic hyperplasia, by permitting less hindered urine flow. Another utility of the instant compounds is provided by combination with a human 5-alpha reductase inhibitory compound, such that both acute and chronic relief from the effects of benign prostatic hyperplasia are achieved.

Triphosgene was decomposed quantitatively to phosgene by chloride ion. The reaction course was monitored by IR spectroscopy (React-IR), showing that diphosgene was an intermediate. The methanolysis of triphosgene in deuterated chloroform, monitored by proton NMR spectroscopy, gave methyl chloroformate and methyl 1,1,1-trichloromethyl carbonate in about a 1:1 ratio, as primary products. The reaction carried out in the presence of large excess of methanol (0.3 M, 30 equiv) was a pseudo-first-order process with a k(obs) of 1.0 x 10-4 s-1. Under the same conditions, values of k(obs) of 0.9 x 10-3 s-1 and 1.7 x 10-2 s-1 for the methanolysis of diphosgene and phosgene, respectively, were determined. The experimental data suggest that, under these conditions, the maximum concentration of phosgene during the methanolysis of triphosgene and diphosgene was lower than 1 x 10-5 M. Methyl 1,1,1-trichloromethyl carbonate was synthesized and characterized also by the APCI-MS technique.

The present application describes novel lactams and derivatives thereof of formula I: or pharmaceutically acceptable salt forms thereof, wherein rings ring B is a 4-8 membered cyclic amide containing from 0-3 additional heteroatoms selected from N, O, and S, which are useful as metalloprotease inhibitors.

The invention relates to the products of formula (I): STR1 in which: R1 =represents hydrogen, aryl, arylcarbonyl, arylthio, alkylcarbonyl, R2, R3 represent in particular halogen, mercapto, acyl, carboxy, nitro, cyano, amino, carbamoyl, R4, --OR4 with R4 representing in particular hydrogen, alkyl, alkenyl, alkynyl, acyl, amino, --(CH2)m1 --S(O)m2 --X--R10 with m1=0 to 4, m2=0 to 2, X represents a single bond or --NH--, --NH--CO--, --NH--CO--NH--, and R10 represents alkyl, alkenyl or aryl, and Y represents optionally substituted aryl, these products being in all isomer forms and salts, their use as medicaments.

The invention relates to the new use and the new products of formula (I): STR1 in which: R1 =represents hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, formyl, cycloalkyl, optionally interrupted by heteroatoms, R2, R3 represent in particular halogen, mercapto, acyl, carboxy, nitro, cyano, amino, carbamoyl, R4, --OR4 with R4 representing in particular hydrogen, alkyl, alkenyl, alkynyl, acyl, amino, --(CH2)m1 --S(O)m2 --X--R10 with m1=0 to 4, m2=0 to 2, X represents a single bond or --NH--, --NH--CO--, --NH--CO--NH--, and R10 represents alkyl, alkenyl or aryl, and Y represents optionally substituted aryl, these products being in all the isomer forms and the salts, as medicaments.

Alkyl (aryltelluro)formates are effective precursors of oxyacyl, methyl, and primary and secondary alkyl radicals. At room temperature, irradiation of a benzene solution of methyl (aryltelluro)-formates 10-12, 2-methylpropyl (aryltelluro)formates 14 and 15, octyl (phenyltelluro)formate (17), cyclohexyl (aryltelluro)formates 19 and 20, 3β-cholestanyl (aryltelluro)formates 22 and 23, cholesteryl (phenyltelluro)formate (24) and benzyl (phenyltelluro)formate (27) with a 250-W low-pressure mercury lamp leads to the formation of oxyacyl radicals (34), which can be trapped by diphenyl diselenide to give the corresponding alkyl (phenylseleno)formates 13, 16, 18, 21, 24, 26, and 28 with excellent overall conversions. Thermolysis of these telluroformates at 160 °C in the dark leads to the formation of methyl and primary and secondary alkyl aryl tellurides 36-43 in excellent yields. Presumably, these transformations involve oxyacyl radicals, which undergo subsequent decarboxylation at the elevated temperature to afford alkyl radicals, which become involved in further radical chemistry. When 1-(benzylseleno)-5-hexyl (phenyltelluro)formate (44) was thermolysed under these conditions, 2-methylselenane (45) was observed as the sole selenium-containing product, demonstrating the synthetic utility of (aryltelluro)formates as alkyl radical precursors.

A novel synthesis of chloroformate was developed by a palladium-catalyzed reaction of Cl2, CO, and alkyl nitrite in the gas phase.When PdCl2/γ-Al2O3 or PdCl2/SiO2 was employed as a catalyst, chloroformate was formed in good yield and with high selectivity.It was confirmed that the reaction did not proceed via phosgene.Cl2 is directly converted to methyl chloroformate.No HCl was formed.The reaction temperature greatly influenced the formation rate of chloroformate, and its selectivity depended on the nitrite/Cl molar ratio very drastically.The dependence of the formation rate on the concentrations of CO and methyl nitrite was also examined.

A novel synthesis of chloroformate was developed by palladium-catalyzed reaction of XCl (X=H or NO), CO, and alkyl nitrite in the gas phase.When PdCl2/γ-Al2O3 or PdCl2/SiO2 was used as a catalyst, chloroformate was produced in good yield and with high selectivity.The reaction temperature had a strong influence on the formation rate of chloroformate, and its selectivity drastically depended on the nitrite/chloride ratio.When the nitrite/chloride ratio was less than 2, the selectivity of chloroformate was almost 100percent.Dependence of the formation rate on the concentrations of CO and methyl nitrite was also examined.

ClCOOCH3 has been obtained in very good yield by reaction of (L2 = 2,2'-bipyridine (bipy) or 1,10-phenanthroline (phen)> with CuCl2.The in situ reaction of ClCOOCH3 with alcohols or amines produces carbonates or carbamates.

In the reaction of methanol with phosgene without a solvent with the reagents at comparable initial concentrations in the range of 169-288 K "stepwise" reaction is observed with limiting degrees of conversion of 25, 33 and 50percent with respect to the alcohol.This is due to the formation of fairly stable associates (CH3OH)n*HCl (n = 1, 2, 3), which do not enter into reaction with phosgene.An MNDO/HB quantum-chemical calculation of the self-associates of methanol and their associates with hydrogen chloride was undertaken and confirmed the likely mechanism of the process.

Pesticidal bicyclo-octanes are of the formula STR1 where R is a substituted or unsubstituted aliphatic or aromatic group, R' and R3 are H or a substituted or unsubstituted aliphatic or aromatic group, R2 is a substituted or unsubstituted heterocyclic group containing at least one ring nitrogen and is preferably a 3- or 4- pyridyl group, Z is CH2 CH2, CH2 O--CH2 S or COCH2 or CH(OR5)CH2 where R5 is H, alkyl, acyl or carbamoyl at Y and Y' are O or S(O)m where m is 0, 1 or 2. Various methods for their preparation are described.

The results of an IR and Raman study of normal chloromethylformate, HCOOCH2Cl, and the deuterated derivative HCOOCD2Cl are reported.A minor alteration to the assignments previously published is proposed.It was observed that this molecule exhibits two different crystalline phases, the IR spectra of which show pronounced polarisation effects.These dichroic spectra, however, give no information on the molecular conformation of crystalline chloromethylformate.The (s-cis, gauche) conformation of gaseous CMF was established by harmonic rigid rotor asymmetric top simulation of the IR vapour phase contours.No evidence was found for free or nearly free internal rotation of the CH2Cl group, which was suggested by previous ab initio calculations.

There are described new condensed diazepinones of general formula STR1 wherein B represents one of the divalent groups STR2 and D represents the groups STR3 and X1, X2 represents a =CH-- group or, if B assumes the meaning of the divalent group S, U or W, they may also represent an N atom, A1 and A2 in general represent lower alkylene groups, Z represents a C--C bond or the groups, --O--, --S--, --CH2 --, or --(CH2)2 --; R represents hydrogen or methyl, R1 and R2 generally represent alkyl groups which, together with the nitrogen atom between them, may also form a saturated monocylic, heterocyclic group, R3 represents alkyl, chlorine or hydrogen, R4 represents hydrogen or methyl, R5 and R6 represent hydrogen, halogen or alkyl, R7 represents hydrogen, chlorine or methyl, R8 represents hydrogen or lower alkyl, R9 represents hydrogen, halogen, lower alkyl and R10 represents hydrogen or methyl and R12 represents branched or unbranched alkyl. The compounds of general formula I and the acid addition salts thereof may be resolved into their isomers. The compounds of formula I and their salts may be used as vagal pacemakers for the treatment of bradycardia and bradyarrhythmia.

Irradiation of 5-methyl-2-(α-methyalkenoyl)-1,4-benzoquinones in alcohol under anaerobic conditions gave the two isomers of chromone derivatives being isomerization products of the quinones.Besides them other two adducts were produced.The mechanism of the formation of these products is discussed.

A quantitative analysis of the effect of the characteristics of the medium on the phosgenation rate of alcohols was made by means of the parameters of the Koppel-Palm equation.An equation is proposed which describes the effect of the solvent on the reaction rate and which takes account of the interdependence of the components of nonspecific and specific solvation.The applicability of the proposed equation to other solvolytic reactions was demonstrated.An equation is obtained which makes it possible to asses the phosgenation rate of alcohols in relation to the properties of the medium and the structure of the alcohol.

Reactions of tributyltin methoxide with esters RCO2R' (R'=CH2Cl, CHCl2 or CCl3) have been performed to study the influence of the halogens in the alkyl component of an ester on the course of the reaction.In all reactions tributyltin chloride and methyl ester were formed whereas the subsequent reaction depended on the number of halogens in the methyl group.

Heterocyclic compounds of the formula STR1 wherein Het denotes optionally substituted pyridazinyl, pyrimidinyl, pyrazinyl or substituted pyridyl, R1 is hydrogen or methyl and R2 is lower alklyl, optionally substituted phenyl-lower alkyl, carboxy-lower alkyl or functionally modified carboxy-lower alkyl, their condensation products with aldehydes, ketones or carbonic acid and their N-oxides, which are valuable (cardioselective) β-receptor blocking agents, and/or (cardioselective) β-receptor-stimulants.

The kinetics of the reaction of phosgene with various aliphatic alcohols were investigated in heptane and dioxane and without a solvent.The effects of the polarity of the medium the structure of the alcohol, and the activation parameters of the process are consistent with an addition-elimination mechanism.

Heterocyclic compounds of the formula STR1 wherein Het denotes optionally substituted pyridazinyl, pyrimidinyl, pyrazinyl or substituted pyridyl, R 1 is hydrogen or methyl and R 2 is lower alkyl, optionally substituted phenyl-lower alkyl, carboxy-lower alkyl or functionally modified carboxy-lower alkyl, their condensation products with aldehydes, ketones or carbonic acid and their N-oxides, which are valuable (cardioselective) β-rezeptor blocking agents, and/or (cardioselective) β-rezeptor-stimulants.

A naphthalimide derivative having the formula STR1 wherein R is an alkyl, or cycloalkyl, an aralkyl, a haloalkyl, an alkoxyalkyl, a hydroxyalkyl, an N,N-dialkylaminoalkyl, an unsubstituted or halogen-, alkyl-, alkoxy- or hydroxy-substituted aryl, or an ammoniumalkyl; X is a group of the formula, STR2 wherein A is STR3 or an unsubstituted or halogen-substituted arylene, or a group of the formula, STR4 wherein R1 is hydrogen, an alkyl, phenyl, a hydroxyalkyl, or an alkoxyalkyl; Y is --CO--, --COO--, --CONR3 -- (where R3 is hydrogen or an alkyl), or --SO2 --; R2 is hydrogen, an alkyl, a cycloalkyl, an aralkyl, a haloalkyl, an alkyl- or aryl-substituted amino-alkyl, an unsubstituted or halogen-, alkyl-, alkoxy-, hydroxy-, amino- or alkylamino-substituted aryl, a group of the formula, STR5 (where R, R1 and Y are as defined above and R4 is a bivalent group), or a group of the formula, (where R5 is direct linkage or a bivalent group; Q+ is a substituted ammonium, a cycloammonium or a hydrazinium; and α- is an anion), Which is useful for optically brightening an organic polymer material.

The compounds are N-piperidinyl and pyrrolidinyl-9-xanthenylamines which are inhibitors of gastric acid secretion.

N-Substituted 1,4-dihydropyridines are prepared by reaction of the corresponding N-unsubstituted 1,4-dihydropyridines with an alkyl haloformate, an acid halide or a carbamyl halide in the presence of base. These compounds have hypotensive activity.

Compounds of the formula: EQU1 wherein R and R1 represent alkyl of 1 through 4 carbon atoms, X1 and Y1 represent oxygen or sulphur, and X2 and Y2 represent oxygen or sulphur, at least one of X2 and Y2 representing sulphur, possess fungicidal and anthelmintic properties.