1518-86-1

Direct reductive amination of prochiral ketones catalyzed by amine dehydrogenases is attractive in the synthesis of active pharmaceutical ingredients. Here, we report the protein engineering of L-Bacillus cereus amine dehydrogenase to allow reactivity on synthetically useful aromatic ketone substrates using an iterative, multiple-site alanine scanning mutagenesis approach. Mutagenesis libraries based on molecular docking, iterative alanine scanning, and double-proximity filter approach significantly expand the scope of active pharmaceutical ingredients relevant building blocks. The eventual quintuple mutant (A115G/T136A/L42A/V296A/V293A) showed reactivity toward aromatic ketones 12 a (5-phenyl-pentan-2-one) and 13 a (6-phenyl-hexan-2-one), which have not been reported to serve as targets of reductive amination by currently available amine dehydrogenases. Docking simulation and tunnel analysis provided valuable insights into the source of the acquired specificity and activity.

The present invention provides compounds useful as inhibitors of AHR, compositions thereof, and methods of using the same.

The invention provides an improved synthetic method of (R)-1-aryl-2-propylamine. The improved synthetic method comprises the following steps of: adopting 1-arylacetone as a raw material, adding (R)-1-phenylethylamine, carrying out reductive amination reaction with hydrogen under a common action of a Lewis acid additive and a transitional metal hydrogenation catalyst; carrying out Pd/C catalytic hydrogenation on an obtained intermediate to remove phenethyl on nitrogen and thus obtaining (R)-1-aryl-2-propylamine. The improved synthetic method provided by the invention has the beneficial effectsthat the operation is simple, the adopted Lewis acid additive is low in cost and easy in obtaining, the yield and the enantioselectivity of a product are high, and the application value for industrialsynthesis of (R)-1-aryl-2-propylamine is very high.

Polyfunctional indoles bearing substituents at C5 and C6 are prevalent in natural products, pharmaceuticals, agrochemicals, and materials. Owing to the remoteness of the C5 and C6 positions, indoles of this family can be difficult to prepare, and often require multistep syntheses. Herein, we describe a concise process that converts simple derivatives of tyrosine into 5,6-difunctionalized indoles by direct oxidation of C?H, N?H, and O?H bonds. Our work draws inspiration from the biosynthetic polymerization of tyrosine to make melanin pigments, but makes an important departure to provide well-defined indole heterocycles.

The development of base metal catalysts for the synthesis of pharmaceutically relevant compounds remains an important goal of chemical research. Here, we report that cobalt nanoparticles encapsulated by a graphitic shell are broadly effective reductive amination catalysts. Their convenient and practical preparation entailed template assembly of cobaltdiamine- dicarboxylic acid metal organic frameworks on carbon and subsequent pyrolysis under inert atmosphere.The resulting stable and reusable catalysts were active for synthesis of primary, secondary, tertiary, and N-methylamines (more than 140 examples).The reaction couples easily accessible carbonyl compounds (aldehydes and ketones) with ammonia, amines, or nitro compounds, and molecular hydrogen under industrially viable and scalable conditions, offering cost-effective access to numerous amines, amino acid derivatives, and more complex drug targets.

The invention relates to new azetidine derivatives of the formula (I) wherein Ar1, Ar2, X, R, T and L are as defined in the description, to their use as medicaments, to methods for their therapeutic use and to pharmaceutical compositions containing them.

Azetidine derivatives of which the following is exemplary and their use in the treatment of obesity, diabetes or dyslipidemia.

Both enantiomers of several phenylethylamines, structurally related to amphetamine, have been prepared in good yields and excellent enantiomeric purity by enzymatic kinetic resolution using CAL-B and ethyl methoxyacetate as the acyl donor. In the case of the 4-hydroxyderivative of amphetamine (compound 4i), the S enantiomer racemized possibly in a dynamic kinetic resolution (DKR) under the enzymatic conditions used. The Royal Society of Chemistry 2011.

The present invention provides a compound of formula (I): wherein: ? R1 is a group selected from -CH2OH,-NH(CO)H and ? R2 is a hydrogen atom; or ? R1together with R2 form the group -NH-C(O)-CH=CH-, wherein the nitrogen atom is bound to the carbon atom in the phenyl ring holding R1and the carbon atom is bound to the carbon atom in the phenyl ring holding R2 ? R3a and R3bare independently selected from the group consisting of hydrogen atoms and C1-4alkyl groups, ? n represents an integer from 1 to 3; ? Ad represents 1-adamantyl or 2-adamantyl group, or a pharmaceutically-acceptable salt or solvate or stereoisomer thereof.

Various aldoximes and ketoximes were selectively reduced to the corresponding amines by catalytic transfer hydrogenation employing low cost magnesium powder and ammonium formate at room temperature. Many other functionalities such as halogens, -OH, -OCH3, -COOH and -CH 3 remained unaffected. The hydrogenation is fast, mild, clean, cost effective and high yielding.

The 18F-labeled β2-adrenergic receptor ligand (R,R)(S,S) 5-(2-(2-[4-(2-[18F]fluoroethoxy)phenyl]-1-methylethylamino)- 1-hydroxyethyl)-benzene-1,3-diol, a derivative of the original highly selective racemic fenoterol, was synthesized in an overall radiochemical yield of 20% after 65 min with a radiochemical purity higher than 98%. The specific activity was in the range of 50-60 GBq/μmol. In vitro testing of the non-radioactive fluorinated fenoterol derivative with isolated guinea pig trachea was conducted to obtain an IC50 value of 60 nM. Preliminary ex vivo organ distribution and in vivo experiments with positron emission tomography (PET) on guinea pigs were performed to study the biodistribution as well as the displacement of the radiotracer to prove specific binding to the β2-receptor.

Various oximes, both aldoximes and ketoximes, are selectively reduced to corresponding amines employing low cost zinc dust and ammonium formate despite presence of other functional groups such as halogens, -OH, -OCH3, -COOH, -CN, > C = C 3.

1. Amphetamine (AM) and five amphetamine derivatives, N-ethylamphetamine (NEA), N-butylamphetamine (NBA), 4-methoxyamphetamine (M-AM), 4-methoxy-N-ethylamphetamine (M-NEA) and 4-methoxy-N-butylamphetamine (M-NBA) were incubated with microsomal preparations from cells expressing human CYP2D6 to determine whether the enzyme was capable of catalyzing the direct ring oxidation of all substrates; the N-dealkylation of NEA, NBA, M-NEA and M-NBA; and the O-demethylation of M-AM, M-NEA and M-NBA. 2. None of the six compounds examined was N-dealkylated to any extent. 3. The only metabolites produced from AM, NEA and NBA were the corresponding ring 4-hydroxylated compounds, and the rates of formation were low. 4. All ring 4-methoxylated substrates were efficiently O-demethylated by CYP2D6 to their corresponding phenols. The size of the N-alkyl group influenced the rates of formation of these phenolamines. In contrast to reported findings with 2- and 3-methoxyamphetamines, none of the 4-methoxyamphetamines was ring-oxidized in the CYP2D6 enzyme system to 2- or 3-hydroxy-4-methoxyamphetamines or to dihydroxy-amphetamines.

After oral administration of 3,7-dihydro-1,3-dimethyl-7-2[(1-methyl-2-phenylethyl)-amino-ethyl]-1H -purine-2,6-dione (fenetylline, Captagon), 7 new metabolites could be detected in urine besides 4 known substances. The metabolites were identified by gas chromatography (GC) and by comparison of the mass spectra (MS) of metabolites with those of authentic reference compounds using a combined GC/MS method.

Micriorganisms which hydrogenate 2-nitro-1-phenyl-1-propene were screend in type cultures and soil samples.Some actinomycetes belonging to Rhodococcus, Nocardia and Mycobacterium asymmetrically reduced the substrate and gave optically active 2-nitro-1-phenylpropane.Among them, Rhodococcus rhodochrous IFO 3338 gave the best results.The satureted compound was obtained quantitatively, when cultivation was carried out for 3 days at 30 oC with a substrate concentration of 0.4percent.The optical purity of the product was seriously affected by the pH of the medium.The more acidic the medium, the higher the enantiomeric excess.The results suggested that non-enzymatic racemization of the product take place even under neutral conditions.Other substrates, such as 2-nitro-1-propene were also converted to optically active 2-nitro-1-substituted propane.

An aromatic L-amino acid decarboxylase was crystallized from the cell free extract of Micrococcus percitreus.The purification procedure included protamine sulfate treatment, ammonium sulfate fractionation, DEAE-Sephadex column chromatography and Sephadex G-200 filtration.Crystals were obtained from a solution of the purified enzyme by addition of ammonium sulfate.The crystalline enzyme preparation was homogeneous as judged by ultracentrifugation and SDS-polyacrylamide gel electrophoresis.The molecular weight was determined to be approximately 101,000.The enzyme was evidently composed of two identical subunits of a molecular weight of 48,000.The enzyme catalyzed the stoichiometric conversion of L-tryptophan to tryptamine and CO2 in the presence of pyridoxal phosphate.The optimum pH was 9.0 for the conversion.The Km value and the maximum velocity of L-tryptophan decarboxylation were 2.4E-3 M and 44 μmol/min/mg of protein, respectively.This enzyme also catalyzed decarboxylation of 5-hydroxy-L-tryptophan, L-phenylalanine, L-tyrosine, 3,4-dihydroxy-L-phenylalanine, L-kynurenine and thier α-methyl amino acid derivatives.

Highly purified rat liver mitochondria catalyze oxidative dealkylation of N,N-dimethylamphetamine (I) and Methamphetamine (II). The demethylase activity is bound to the mitochondrial inner membrane or its matrix. Demethylation of N,N-dimethylaniline (1.231 nmol/mg/min) follows about two times faster than dealkylation of I (0.929 nmol/mg/min) or II (0.878 nmol/mg/min). Nitrazepam and other N-alkylamides seem to be no substrates for this mitochondrial enzyme at all. Under aerobic incubation conditions the rate of mitochondrial I-metabolism was about 1/8 of the microsomal rate, provided that both preparations have the same protein concentrations. NADPH was a much better cofactor for this reaction than NADH. The role of cytochrome P-450 as a possible essential cofactor for mitochondrial dealkylation could not be elucidated.

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The present invention is concerned with the production of novel derivatives of thyroid hormones which are useful in the radioimmunoassay (RIA) of such hormones. The invention is particularly concerned with derivatives of thyroxine and triiodothyronine which contain an additional phenol group which is readily iodinatable so that the phenol conjugate can be readily tagged with a radioactive iodine isotope, such as 125 I or 131 I, without detrimentally interfering with the ability of the tagged conjugate so competitively bind with the naturally occurring thyroid hormone in the biological liquid to be analyzed by RIA technique. The invention is also concerned with the iodine-tagged derivatives or conjugates.