Gastro-intestinal absorption of ethyl 2-chloro-3-[4-(2-methyl-2-phenylpropyloxy)phenyl]propionate from different dosage forms in rats and dogs

To obtain information as to a suitable formulation of ethyl 2-chloro-3-[4-(2-methyl-2-phenylpropyloxy)-phenyl]propionate (AL-294), an antihyperlipidemic drug of low water solubility, the bioavailability after its oral administration in various dosage forms was evaluated in rats and dogs. After AL-294 was administered orally, AL-294 acid (2-chloro-3-[4-(2-methyl-2-phenylpropyloxy)phenyl]propionic acid), which is a metabolite of AL-294, was detected in the plasma. Therefore, absorbability of AL-294 was evaluated using plasma AL-294 acid levels. AL-294 in an oil solution or in a gelatin capsule showed poor absorption, whereas it's absorption was greatly enhanced in the form of an emulsion. The postprandial administration also showed better absorption. The elimination rate of AL-294 acid from the plasma after oral administration of the emulsion was similar to that after intravenous administration of a sodium salt of AL-294 acid.     

Effects of the physicochemical properties of the emulsion formulation on the bioavailability of ethyl 2-chloro-3-[4-(2-methyl-2-phenylpropyloxy)phenyl]propionate in rats

The effect of the physicochemical properties of the emulsion formulation on the absorption of ethyl 2-chloro-3-[4-(2-methyl-2-phenylpropyloxy)phenyl]propionate (AL-294) in rats and dogs was studied. When emulsions of different particle sizes were administered to rats, the higher the ratio of Tween-80 to the drug was, the smaller was the particle size and the higher was the absorption. When the emulsions of similar particle size (2 microns) with different Tween-80 ratios were administered to rats, no significant difference was observed in the extent of absorption. The absorption of AL-294 was correlated with the dissolution rate from the oil phase to the aqueous phase but not correlated with the amount of AL-294 solubilized by Tween-80. These results indicate that the absorption of AL-294 from emulsions depends mainly on the particle size in the gastro-intestinal fluid and that Tween-80 serves only to reduce the particle size in the emulsion.     

Chemiluminescence Triggered by Hydrolase Activity in a Horseradish Peroxidase/H2O2-Coupled Assay*

2-Methyl-1-propenyl acetate (MPA) was hydrolyzed by wheat lipase, pancreatic lipase, hydrolases and lipopro-tein lipase from serum in a reaction that produces 2-methyl-1-propenol. The latter was subsequently oxidized by horseradish peroxidase (HRP)/H₂O₂/O₂ yielding triplet acetone that emits visible light. The integrated light emission was proportional to the units of lipase or volume of serum present. When pancreatic lipase was assayed, light emission was observed in the presence of bile salt as surfactant and chlorophyll a as light sensitizer. The potential application of this reaction in determinations of hydrolase/Iipase activities is discussed.     

Reaction of 6-chloro-2-[1-methyl-2-(N-methylthiocarbamoyl)]-hydrazinoquinoxaline 4-oxide with dimethyl acetylenedicarboxylate

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 4a with methyl or phenyl isothiocyanate gave 6-chloro-2-[1-methyl-2-(N-methylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 7a or 6-chloro-2-[1-methyl-2-(N-phenylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 7b , respectively, whose reaction with dimethyl acetylenedicarboxylate afforded 6-chloro-2-[N-methyl-N-(5-methoxycarbonylmethylene-3-methyl-4-oxo-2-thioxoimidazolidin-1-yl)]aminoquinoxaline 4-oxide 8a or 6-chloro-2-[N-methyl-N-(5-methoxycarbonylmethylene-4-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)]aminoquinoxaline 4-oxide 8b , respectively.     

Effect of acyl chain length and branching on the enantioselectivity of Candida rugosa lipase in the kinetic resolution of 4-(2-difluoromethoxyphenyl)-substituted 1,4-dihydropyridine 3,5-diesters.

Since 2,6-dimethyl-4-aryl-1,4-dihydropyridine 3,5-diesters themselves are not hydrolyzed by commercially available hydrolases, derivatives with spacers containing a hydrolyzable group were prepared. Seven acyloxymethyl esters of 5-methyl- and 5-(2-propoxyethyl) 4-[2-(difluoromethoxy)phenyl]-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate were synthesized and subjected to Candida rugosa lipase (CRL) catalyzed hydrolysis in wet diisopropyl ether. A methyl ester at the 5-position and a long or branched acyl chain at C3 gave the highest enantiomeric ratio (E values). The most stereoselective reaction (E = 21) was obtained with 3-[(isobutyryloxy)methyl] 5-methyl 4-(2-difluoromethoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, and this compound was used to prepare both enantiomers of 3-methyl 5-(2-propoxyethyl) 4-[2-(difluoromethoxy)phenyl]-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate. The absolute configuration of the enzymatically produced carboxylic acid was established to be 4R by X-ray crystallographic analysis of its 1-(R)-phenylethyl amide.     

A new method for the synthesis of 4H-1,3,4-thiadiazino[5,6-b]quinoxalines

The reaction of 6-chloro-2-[1-methyl-2-(Mmemylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 5 with acetic anhydride or trifluoroacetic anhydride resulted in dehydrative cyclization to give 2-(N-acetyl)-memylamino-8-chloro-4-methyl-4H-1,3,4-thiadiazino[5,6-b]quinoxaline 6 or 8-chloro-2-(N-trifluoroacetyl)methylamino-4-methyl-4H-1,3,4-thiadiazino[5,6-b]quinoxaline 9 , respectively. The oxidation of compound 6 or 9 with 2-fold molar amount of m-chloroperbenzoic acid afforded the 4H-1,3,4-thiadiazino-[5,6-b]quinoxaline 1,1-dioxide 8 or 13 , respectively. The acetyl group of compound 6 was hardly hydrolyzed, but the trifluoroacetyl group of compound 9 was easily hydrolyzed to change into 8-chloro-4-methyl-2-memylamino-4H-1,3,4-thiadiazino[5,6-b]quinoxaline 10 . The acylation of compound 10 with acetic anhydride, trifluoroacetic anhydride, phenyl isocyanate, and chloroacetyl chloride furnished the 2-(N-acetyl)methylamino 6 , 2-(N-trifluoroacetyl)methylamino 9 , 2-(1-methyl-3-phenylureido) 11 , and 2-(N-chloroacetyl)methylamino 12 derivatives, respectively.     

Condensed pyridazines. Part III. Rearrangement and ring cyclization during the thermolysis of (z)-methyl 3-(6-azido-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazin-5-yl)-2-methylacrylate

The thermolysis of (Z)-methyl 3-(6-azido-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazin-5-yl)-2-methylacrylate ( II ) provides a new synthetic route to pyrrolo[2,3-c-]pyridazines, specifically, methyl 3-chloro-1,6-dimethyl-4-oxo-1,4-dihydro-7H-pyrrolo[2,3-c]pyridazine-5-carboxylate ( III ) in 91% yield. Treatment of III with ozone provides an entry into the novel pyridazino[3,4-d][1,3]oxazine ring system, specifically, 3-chloro-1,7-dimethylpyridazino[3,4-d][1,3]oxazine-4,5-dione ( IV ) in 73% yield. Compound IV is smoothly hydrolyzed into 6-acetylamino-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazine-5-carboxylic acid ( V ) which is readily recyclized into IV by dehydration with acetic anhydride. Furthermore, IV undergoes a facile reductive ring opening reaction with sodium borohydride to give 3-chloro-6-ethylamino-1-methyl-4-oxo-1,4-dihydropyridazine-5-carboxylic acid ( VI ) in 95% yield.     

Synthesis of halosulfuron-methyl via selective chlorination at 3- and/or 5-position of pyrazole-4-carboxylates

Reactions of methyl pyrazole-4-carboxylates 4b-d with N-chlorosuccinimide under heating conditions without a solvent gave methyl 3,5-dichloro-1-methylpyrazole-4-carboxylate 4a in good yields. The reaction of 4a with sodium hydrosulfide led to a nucleophilic substitution on the 5-position regioselectively to afford methyl 3-chloro-1-methyl-5-mercaptopyrazole-4-carboxylate 6a, which was followed by oxidative chlorination and amination to obtain 3-chloro-1-methyl-5-sulfamoylpyrazole-4-carboxylate 2a. Finally, the reaction of 2a with phenyl 4,6-dimethoxypyrimidin-2-yl carbamate 7 provided methyl 3-chloro-5-(4,6-dimethoxypyrimidin-2-ylcarbamoylsulfamoyl)-1-methylpyrazole-4-carboxylate (halosulfuron-methyl) 1a promising herbicide in com.     

Syntheses Based on 4-Chloro-1-[3,5-di(trifluoromethyl)phenyl]-, 4-Chloro-1-(2,4-difluorophenyl)-5-formyl-3-methyl-6,7-dihydroindazoles,and 4-Chloro-5-formyl-3-methyl-1-(2-pyridyl)-6,7-dihydroindazoles

Vilsmeier formylation of 1-[3,5-di(trifluoromethyl)phenyl]- and 1-(2,4-difluorophenyl)-3-methyl-4-oxo-4,5,6,7-tetrahydroindazoles gave the corresponding 1-aryl-4-chloro-5-formyl-3-methyl-6,7-dihydroindazoles. Reaction of the latter with amidines, o-phenylenediamine, hydrazine, or hydroxylamine gave a series of 1-aryl-3-methyl-6,6-dihydroindazoles annelated at positions 4 and 5. The reaction of 4-chloro-5-formyl-3-methyl-1-(2-pyridyl)-6,7-dihydroindazole with substituted anilines gave 5-arylaminomethylene-4-oxo- or 5-arylaminomethylene-4-arylimino-3-methyl-1-(2-pyridyl)-4,5,6,7-tetrahydroindazoles depending on the molar ratio of reagents and the nucleophilicity of the amines.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 740–750, May, 2005.     

Synthesis and some transformations of halogen-substituted o-quinones in the benzofuran series

The corresponding 6-halo-substituted o-quinones were obtained by the action of nitric acid on 2-methyl(phenyl)-3-carbethoxy-4,6-dihalo-5-hydroxybenzofurans, whereas 2-methyl-3-carboxy-4,6-dibromo-5-hydroxybenzofuran is converted to the 4,6-dinitro derivative under similar conditions. The action of nitric acid on 2-methyl-3-carbethoxy-4-chloro-5-hydroxybenzofuran leads to replacement of the hydrogen in the 6 position by a nitro group. The reduction of o-quinones to the corresponding dihydroxy derivatives and reactions of quinones with amines are described.     

Synthesis and modification of 4-hydroxy-2-methyl-3-(2-chloro-2-propenyl)quinoline

4-Hydroxy-2-methyl-3-(2-chloro-2-propenyl)quinoline was prepared by O-allylation of 4-hydroxy-2-methylquinoline followed by the Claisen rearrangement of the 2-methyl-4-(2-chloro-2-propenyloxy)quinoline obtained. Chemical modifications of 4-hydroxy-2-methyl-3-(2-chloro-2-propenyl)quinoline resulted in the synthesis of 4-amino-2-methyl-3-(2-methyl-3-indolyl)quinoline.     

Synthesis of mesoionic triazolo[4,3-a]quinoxalines

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 1 or 6-chloro-2-(1-methylhydrazino)-quinoxaline 5 with phenyl isothiocyanate under reflux in N,N-dimethylformamide gave 7-chloro-3-methyl-1,2,4-triazolo[4,3-a]quinoxalin-3-ium-1-thioate 4 , which was also obtained by refluxing of 6-chloro-2-[1-methyl-2-(N-phenylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 2b or 6-chloro-2-[1-methyl-2-(N-phenylthiocarbamoyl)hydrazino]quinoxaline 6 in N,N-dimethylformamide.     

Synthesis of 2-[3′-(trifluoromethyl)anilino] -5-hydroxynicotinic acid

2-[3′-(Trifluoromethyl)anilino]-5-hydroxynicotinic acid (2) was synthesized by two routes: a) by direct hydroxylation of 2-[3′-(trifluoromethyl)anilino]nicotinie acid (1) ; and b) by the following sequence starting from 2-chloro-3-methyl-5-nitropyridine (3) via 5-amino-2-chloro-3-methylpyridine (4) , 2-ehloro-5-hydroxy-3-methylpyridine (6) , 5-acetoxy-2-chloro-3-methylpyridine (7) , 5-acetoxy-2-chloronicotinie acid (8) , and 2-chloro-5-hydroxynicotinic acid (9). The correlation of 2 with one of the metabolites of 1 has been accomplished, and the identities of both compounds have been proven.     

Synthesis of new modified aza heterocycles on the basis of 5-(2-chloro-1-nitroalkyl)-3-phenyl-and 5-(2-chloro-1-nitroalkyl)-3-methyl-1,2,4-oxadiazoles

3-Phenyl-and 3-methyl-5-(2-chloro-1-nitroalkyl)-1,2,4-oxadiazoles reacted with piperidine, pyrrolidine, and morpholine to give the corresponding 5-(2-amino-1-nitroalkyl) derivatives, while their reactions with sodium p-toluenesulfinate led to the formation of 2-[3-methyl(or phenyl)-1,2,4-oxadiazol-5-yl]-2-nitroethyl p-tolyl sulfones.     

有机相酶催化拆分制备(S)-2-氯-1-(2-噻吩)-乙醇

首次在有机相中对酶催化条件下的2-氯-1-(2-噻吩)-乙醇的反应进行了研究. 通过对不同来源酶的筛选, 找到了Novozym 435和Alcaligenes sp两种选择性较好的酶, 它们均对该反应具有较高的选择性和较快的反应速度, 在此基础上进一步通过对溶剂、温度、摇床转速以及酶用量的筛选, 确定了能够有效拆分2-氯-1-(2-噻吩)-乙醇的较佳反应条件. 当温度35 ℃, 酶量10 mg/mL, 反应72.5 h, 产物的ee值为98.5%时收率为48.6%.     

Fluorimetric analysis of lipase hydrolysis of intermediate- and long-chain glycerides

For the purpose of deducing the digestive behavior of dietary fat in the digestive organs, a fluorimetric method for the measurement of hydrolysis by porcine pancreatic lipase was performed using intermediate- and long- acyl chain glycerides as substrates. Insoluble glycerides constituted by C10-C16 acyl chains were mechanically dispersed in 100% buffer and hydrolyzed by porcine pancreatic lipase. After the reaction, fatty acid released by the enzyme was extracted and its carboxyl group was fluorescently labeled with 9-bromomethylacridine. The 9-acridinylmethyl derivative of the fatty acid was separated and determined by HPLC. The sensitivity of this method was about 1000 times higher than that of the titrimetric method. Only 0.5 ng of porcine pancreatic lipase was sufficient for one routine assay. This assay method was successfully applied to investigate the enzymatic properties of porcine pancreatic lipase with respect to dietary lipids. The effects of some physiological factors concerned with lipid digestion, such as bile salt and colipase, on the lipase hydrolysis were also examined. The method established in the present study could contribute to a highly sensitive assay of some hydrolases containing lipase with regard to insoluble substrates.     

Syntheses of 2-chloro-4-nitrophenyl beta-D-maltopentaosides with bulky modification and their application to the differential assay of human alpha-amylases.

Four novel maltopentaosides, 2-chloro-4-nitrophenyl O-(6-O-p-toluenesulfonyl-alpha-D-glucopyranosyl)-(1-->4)-tris[O- alpha-D-glucopyranosyl-(1-->4)]-beta-D-glucopyranoside (4), 2-chloro-4-nitrophenyl O-[6-O-(tert-butyldimethyl)silyl-alpha-D- glucopyranosyl]-(1-->4)-tris[O-alpha-D-glucopyranosyl-(1-->4)]-beta-D- glucopyranoside (5), 2-chloro-4-nitrophenyl O-[6-deoxy-6-(phenyl)sulfonyl-alpha-D- glucopyranosyl]-(1-->4)-tris[O-alpha-D-glucopyranosyl-(1-->4)]-beta-D- glucopyranoside (10), and 2-chloro-4-nitrophenyl O-(6-deoxy-6-phthalimido-alpha-D-glucopyranosyl)- (1-->4)-tris[O-alpha-D-glucopyranosyl-(1-->4)]-beta-D-glucopyranoside (11) were synthesized. Substrates 4, 5, 10, and 11 were hydrolyzed by human pancreatic alpha-amylase (HPA) from 1.1 to 2.9-fold faster than by human salivary alpha-amylase (HSA). Taking advantage of the difference in the hydrolytic rate of 5 (2.9-fold faster), we developed a new method for the differential assay of these two human alpha-amylases.     

Synthesis and calcium channel antagonist activity of new symmetrical and asymmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-substituted 1,4-dihydropyridines

New symmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-substituted 1,4-di-hydropyridines were synthesized in moderate to good yields via the modified Hantzsch reaction of β-dicarbonyl compounds with (Z)-3-chloro-3-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)acrolein in the presence of an excess amount of NH₄OAc. Also, the reaction of β-dicarbonyl compounds with (Z)-3-chloro-3-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)acrolein in the presence of enamino esters and ketones was performed, and asymmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-substituted 1,4-dihydropyridines were obtained in moderate to good yields at room temperature. The calcium channel blocking activity of these compounds was assessed. They demonstrated moderate to weak effects, although one compound had a comparable effect (IC₅₀ =1.40×10⁻⁷ M) with respect to the reference drug Nifedipine.     

Reactions of 3-methyl-1-(2-pyridyl)-4-chloro-5-formyl-6,7-dihydroindazole

The reactions of 3-methyl-1-(2-pyridyl)-, 3-methyl-1-phenyl-, and 3-methyl-1,6-diphenyl-4-chloro-5-formyl-6,7-dihydroindazoles with guanidine and benzo- and 3- and 4-pyridinecarbamidines gave the corresponding 8-substituted 1-methyl-3-(2-pyridyl)-and 1-methyl-3-phenyl-4,5-dihydropyrazolo[5,4-h]quinazolines. With acetic anhydride the same indazole derivatives gave the 4-acetoxy-5-formyl derivatives, and with hydroxylamine they gave4-chloro-5-hydroxyiminomethyl-6,7-dihydroindazoles. Thereactionof4-acetoxyl-1-(2-pyridyl)-5-formyl-6,7-dihydroindazole with hydroxylamine gave 8-methyl-6-(2-pyridyl)-4,5-dihydroisoxazolo[5,4-e]indazole, while dehydration of 5-hydroxyiminomethyl-3-methyl-4-chloro-6,7-dihydroindazole gave the 4-chloro-5-cyano derivative. The reaction of the latter with nucleophilic reagents was investigated.Riga Technical University, Riga, Latvia LV-1658. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1209–1213, September, 1998.     

New 4-quinaldinol derivatives XVII. 2-Methyl-3-(3-chloro-2-buten-1-yl)-4-hydroxyquinoline-6-carboxylic acid and some of its transformations

1-(2-Methyl-4-hydroxy-6-carboxy-3-quinolinyl)-3-butanone and 1-(2-methyl-4-chloro-6-carboxy-3-quinolinyl)-3-butanone were obtained by the acid hydrolysis of 2-methyl-3-(3-chloro-2-buten-1-yl)-4-hydroxy(chloro)quinoline-6-carboxylic acids and their esters.See [6] for communication XVI.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1681–1682, December, 1971.