Synthesis and antiulcer activity of optical isomers of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid (rebamipide).

The enantiomers of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl] propionic acid [(+/-)-1, rebamipide, OPC-12759], a new antiulcer agent that enhances mucosal resistance, were synthesized from optically active alpha-amino acid derivatives of 2(1H)-quinolinone. The key intermediates, alpha-amino acid derivatives, were prepared by asymmetric synthesis and optical resolution. The (+)-1 was about 1.7 times as potent as the (-)-isomer in antiulcer activity against ethanol-induced gastric ulcers.     

Synthesis and biological activities of optical isomers of 2-(4-chlorophenyl)-5,6-dihydro-(1)benzothiepino[5,4-c]pyridazin-3(2H)-o ne 7-oxide.

Two enantiomers of 2-(4-chlorophenyl)-5,6-dihydro-(1)benzothiepino[5,4- c]pyridazin-3(2H)-one 7-oxide ((+/-)-1: Y-23684) were synthesized in high yields by asymmetric oxidation of the synthetic precursor (2) using modified Sharpless reagent. Among the oxidants tested, cumene hydroperoxide (CHP) gave the highest optical and chemical yields, while tert-butyl, tert-amyl, and 1,1,3,3-tetramethylbutyl hydroperoxides did not show such high enantio-selectivities. The absolute configuration of (+)-1 enantiomer synthesized from 2, Ti(O-iso-Pr)4, (-)-diethyl tartarate, and CHP was determined to be S by X-ray crystallographic analysis. Both enantiomers, S-(+)-1 and R-(-)-1, and (+/-)-1 had approximately equivalent in vivo activities to antibicuculline test in mice and anticonflict test in rats, although S-( + )-1 showed about three times higher affinity to benzodiazepine receptor than R-(-)-1 in [3H]diazepam binding assay.     

Determination of saterinone enantiomers in plasma samples with an internal standard using a Chiralcel OD column, fractionation and reversed-phase chromatography

A specific and validated high-performance liquid chromatographic method was developed for the determination of the S-(-) and R-(+) enantiomers of saterinone. 1-[(4-cyano-1,2-dihydro-6-methyl-2-oxopyridin-5-yl)phenoxyl] -3-[4-(2- methoxyphenyl)piperazin-1-yl]propan-2-ol, in plasma at the low ng/ml level. The enantiomers of saterinone and an internal standard, 1-[(4-cyano-1,2-dihydro-6-methyl-2-oxo-pyridin-5-yl)phenoxy]-3-[4-(2- ethoxyphenyl)piperazin-1-yl]propan-2-ol, were chromatographed on a chiral Chiralcel OD stationary phase. However, the S-(-) enantiomers of saterinone and the internal standard were unresolved, as were the R-(+) enantiomers of both substances. Therefore, the two fractions were collected and each was separately resolved on an achiral Polyencap A reversed-phase column and quantified. The detection limit was 0.5 ng/ml of enantiomer, allowing the determination of plasma levels up to 36 h after oral administration of 90, 150 and 180 mg of saterinone to twelve subjects.     

Stereospezifität der neuroleptischen Wirkung und Chiralität von (+)-3-{2-[4-(8-Fluor-2-methyl-10,11-dihydrodibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-äthyl}-2-oxazolidinon (16). 4. Mitteilung über tricyclische Antidepressiva und Neuroleptica

Stereospecifity of the neuroleptic activity and chirality of (+)-3-{2-[4-(8-fluoro-2-methyl-10, 11-dihydrodibenzo[b,f]thiepin-10-yl)-1-piperazinyl]ethyl}-2-oxazolidinone (16). The synthesis and stereospecific neuroleptic action in animals of the (+)-enantiomer of 3-{2-[4-(8-fluoro-2-methyl-10,11-dihydrodibenzo [b,f]thiepin-10-yl)-1-piperazinyl]ethyl}-2-oxazolidinone ( 16 ) are briefly described. The (10S)-configuration of this compound was determined by X-ray diffraction.     

New liquid crystal compounds ( )-4-[5-(2-Methylbutyl)-1,3-dioxan-2-yl]phenyl 4-alkoxybenzoate

New liquid crystal compounds, (+)-4-[5-(2-methylbutyl)-1,3-dioxan-2-yl] phenyl 4-alkoxybenzoates (5), were synthesized. The mesomorphic behaviour of these compounds is compared with that of (+)-4-(5-alkyl-1,3-dioxan-2-yl)-phenyl 4-(2-methylbutoxy)benzoates (6). While compounds 6 exhibited a chiral smectic C phase, the corresponding compounds 5 did not. This might mean that for the appearance of a chiral smectic C phase in these types of compounds, it is necessary that the carbonyl and the chiral groups exist at nearby positions. Transition temperatures to those isotropic state for compounds 5 were lower than those for compounds 6. This result is common in both cases of (+)-4-alkoxycarbonylphenyl-4-[5-(2-methylbutyl)-1,3-dioxan-2-yl]benzoates (7), and (+)-4-(2-methylbutoxy-carbonyl)phenyl 4-(5-alkyl-1,3-dioxan-2-yl)-benzoates (8).     

Kinetics and mechanism of ring transformation of S-[1-(4-methoxyphenyl)pyrrolidin-2-on-3-yl]isothiuronium bromide to 2-methylimino-5-[2-(4-methoxyphenylamino)ethyl]thiazolidin-4-one

The kinetics and mechanism of transformation reaction of S-[1-(4- methoxyphenyl)pyrrolidin-2-one-3-yl]-N-methyl-isothiuronium bromide into 2-methylimino-5-[2-(4-methoxyphenylamino) ethyl)]thiazolidin-4-one have been studied in aqueous solutions of amine buffers (pH 8.1-11.5) and sodium hydroxide solutions (0.005-0.5 mol l-1) at 25 degrees C and at I = 1 mol l-1 at pseudo-first-order reaction conditions. The kinetics observed shows that the transformation reaction is subject to general base, general acid, and hydroxide-ion catalyses. The rate-limiting step of transformation is the splitting-off a proton from the tetrahedral intermediate In. The value of pKa for S-[1-(4-methoxyphenyl)- pyrrolidin-2-one-3-yl]-N-methylisothiuronium bromide has been determined from the kinetic data (pKa = 8.75 +/- 0.10) and by potentiometric titration (pKa = 8.90 +/- 0.05). With increasing pKa value of the acid buffer component, the value of Br?nsted coefficient beta gradually decreases from about 0.7 to almost zero. The value of pKa approximately 10 for the intermediate to base-catalysed transformation has been found from this dependence. In the N-methylpyrrolidine and triethylamine buffers, the rate-limiting step of transformation is changed into ring opening of In-, and the general-base-catalysed reaction changes into a specific-base-catalysed one.     

N-杂环甲基2-(4-杂芳氧基苯氧基)丙酰胺的合成及除草活性

以2-(4-羟基苯氧)丙酸为原料,设计合成了16个新的手性N-杂环甲基2-(4-杂芳氧基苯氧基)丙酰胺化合物,其化学结构经核磁共振、色谱-质谱、红外光谱及元素分析确证.初步生物活性测定结果表明,合成的化合物在2.25×103g/ha剂量时对单子叶杂草马唐(Digitaria sanguinalis)、稗草(Echinochloa crus-galli)及狗尾草(Setaria viridis)等均具有90%以上的活性;进一步活性及作物安全性测试表明,化合物(R)-(+)-N-[(6-氯吡啶-3-基)甲基]-2-[4-(3-氯-5-三氟甲基吡啶-2-基氧基)苯氧基]丙酰胺(2b)的除草活性高于噁唑酰草胺,且对水稻茎叶处理安全,同时对水稻田主要杂草千金子的活性远高于氰氟草酯;化合物的除草活性与立体构型有关,R构型为活性构型.     

Formation of S-[2-carboxy-1-(1H-imidazol-4-yl) ethyl]glutathione, a new metabolite of L-histidine, from cis-urocanic acid and glutathione by the action of glutathione S-transferase

Exposure of the skin to sunlight results in an increase of the content of epidermal trans-urocanic acid, a key metabolite of L-histidine, and also in occurrence of the isomerization of trans-urocanic acid to the cis isomer. S-[2-Carboxy-1-(1H-imidazol-4-yl)ethyl]glutathione (GS(CIE)), an adduct of urocanic acid and glutathione, is a presumed origin of a urinary compound S-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]-L-cysteine (Cys(CIE)). The formation of GS(CIE) is stimulated by exposing the skin to sunlight irradiation. In this study we investigated an enzymatic formation of GS(CIE) from glutathione and cis-urocanic acid by incubation with rat liver extract that contained glutathione S-transferase (GST) at high activity. The formation of GS(CIE) was suppressed significantly when a liver extract depleted of GST activity was used. Enzymatic degradation of GS(CIE) with gamma -glutamyl transpeptidase resulted in the formation of N-[S-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]-L-cysteinyl]glycine, a metabolic intermediate between the glutathione adduct and Cys(CIE). A hydrolyzed product of GS(CIE) by HCl was identical with the urinary Cys(CIE). Compounds were analyzed by high-voltage paper electrophoresis, capillary electrophoresis, and fast atom bombardment mass spectrometry. From these results, we suggest that GS(CIE) formed from cis-urocanic acid and glutathione is an origin of the urinary compound Cys(CIE) and that the formation reaction is catalyzed mostly by the action of GST.     

Synthesis and calcium antagonistic activity of (+)-(R)- and (-)-(S)-3-acetyl-2-[5-methoxy-2-[4-[N-methyl-N-(3,4,5- trimethoxyphenethyl)amino]butoxy]phenyl]benzothiazoline hydrochloride

SA2572 ((+)-1), 3-acetyl-2-[5-methoxy-2-[4-[N-methyl-N-(3,4,5-trimethoxyphenethyl) amino] butoxy]phenyl]-benzothiazoline hydrochloride is a newly synthesized Ca2+ antagonist having a inhibitory effect on the fast Na+ inward channel. In order to clarify the absolute configurations and the pharmacological properties of both enantiomers, compounds ((+)-1 and (-)-1) were synthesized. The configurations of these compounds were assigned on the basis of an X-ray crystallographic analysis of synthetic precursor (5). The in vitro Ca2+ channel blocking activities of (+)-1 and (-)-1 were evaluated in terms of the inhibitory activities on depolarization-induced contraction of guinea pig taenia cecum and rabbit aorta. The in vivo efficacy of the enantiomers was evaluated with their hypotensive effects in spontaneously hypertensive rats. Compound (-)-1 showed more potent Ca2+ antagonistic activities on guinea pig taenia cecum and rabbit aorta and the hypotensive effect than those activities of (+)-1. In the electrophysiological study of Langendorff perfused rabbit hearts, compound (+)-1 showed more potent inhibitory effect on the fast Na+ inward channel than that of compound (-)-1, and an approximately equal potent inhibitory effect on the slow Ca2+ inward channel as compared with compound (-)-1. Stereoselectivity of the pharmacological activity was found.     

Configurational studies on 2-[∝-(2-ethoxyphenoxy)benzyl] morpholine fce 20124

The relative configuration of the two diastereoisomers of (±)2-[?-(2-ethoxyphenoxy)benzyl] morpholine is determined by a synthesis involving regio and stereo specific reactions. (RS,RS) diastereoisomer FCE 20124 was separated into its (+) and (-) enantiomers both by crystallization of the optically active mandelate salt and by a multi-step synthesis from (+)-(2S,3R)-3-phenylglycidic acid.     

Water-soluble aminoxyls (nitroxides): 2-methyl-2-[(N-(4-tert-butylphenyl)oxyl]propanesulfonate and (1-oxyl-2,5,5-trimethylpyrrolidin-2-yl)methanesulfonate

Two charged aminoxyls, ammonium (1-oxyl-2,5,5-trimethylpyrrolidin-2-yl)methanesulfonate and ammonium 2-methyl-2-[(N-(4-tert-butylphenyl)oxyl]propanesulfonate, obtained by methods easily adaptable to the preparation of various other aminoxyls are totally soluble in water but are partially associated in other solvents.     

Synthesis and oral activity of pivaloyloxymethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3(Z)- (4-methylthiazol-5-yl)vinyl-3-cephem-4-carboxylate (ME1207) and its related compound.

7-[2-(2-Aminothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3(Z)- (4-methylthiazol-5-yl)vinyl-3-cephem-4-carboxylic acid (11, ME1206) and its 3-trans isomer (13) were prepared to test antibacterial activity. These compounds exhibited excellent antibacterial activity against both gram-positive and gram-negative bacteria, including beta-lactamase producing strains. The pivaloyloxymethyl esters (12 and 14) of the compounds (11 and 13) were prepared by esterification with pivaloyloxymethyl iodide. Among them, pivaloyloxymethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]- 3(Z)-(4-methylthiazol-5-yl)vinyl-3-cephem-4-carboxylate (12, ME1207) showed good urinary recovery after oral administration in mice.     

Synthesis and microbial screening of 8-(benzyloxy)-5-(2-[1,3-diphenyl-1H-pyrazol-4-yl]thiazol-4-yl)quinolin-2(1H)-one derivatives

The present investigation describe the synthesis of 8-(benzyloxy)-5-(2-[1,3-diphenyl-1H-pyrazol-4-yl]thiazol-4-yl)quinolin-2(1H)-one derivatives. Quinolin-8-ol was transformed by five step synthetic procedures into 8-Benzyloxy-5-(2-bromo-acetyl)-1H-quinolin-2-one. Subsequently, 8-Benzyloxy-5-(2-bromo-acetyl)-1H-quinolin-2-one condensed with 1,3-Diphenyl-1H-pyrazole-4-carbothioic acid amide in the presence of acetonitrile to afford 8-(benzyloxy)-5-(2-[1,3-diphenyl-1H-pyrazol-4-yl]thiazol-4-yl)quinolin-2(1H)-one derivatives. Synthesized compounds were screened for their antimicrobial activity against gram-positive and gram-negative bacteria. Most of the synthesized compounds are found to be active against tested bacterial strains and fungal strain.     

对映体纯1-甲基-7-氧杂双环[2.2.1]庚烷-2-酮的制备

1-甲基 - 7-氧杂双环 [2 .2 .1 ]庚烷 - 2 -酮 ( 1 )是萜类天然产物全合成中的重要中间体 ,能被广泛地应用于多种桉烷 ( Eudesmane)、沉香呋喃 ( Agarofuran)和降胡萝卜素 ( Norcarotenoids)等倍半萜天然产物的全合成[1,2 ] .我们以对映体纯化合物 1为原料 ,实现这类天然产物的不对称全合成 [3～ 6 ] .消旋的化合物 (± ) - 1可以 2 -甲基呋喃和 2 -氯丙烯腈为原料 ,经 3步反应得到 [2 ] .但对映体纯化合物 1的制备尚未见报道 .本文用化学拆分方法 ,成功地制备了对映体纯的 ( + ) - 1和 ( - ) - 1 ,并确定了其绝对构型 .1　结果与讨论为减…     

Facile Synthesis of Enantiomerically Pure 1-（5-Bromo-2-chlorophenyl）-1-（4-ethoxyphenyl）ethane

A facile 7-step procedure for the synthesis of enantiomerically pure 1-（5-bromo-2-chlorophenyl）-1-（4-ethoxyphenyl）ethanes[（R）-2 and（S）-2] that started from （5-bromo-2-chlorophenyl）（4-ethoxyphenyl）methanone 3 was developed.The key step was the resolution of 2-（5-bromo-2-chlorophenyl）-2-（4-ethoxyphenyl）acetic acid 6 by crystallizations of its L-and D-menthyl esters 7 and 8 from petroleum ether to give optically pure enantiomers 9 and 10,respectively.The absolute configurations of the products were unambiguously determined by single-crystal X-ray diffractions of four key intermediates,9,10,13 and 14.This procedure is characterized by inexpensiveness,scalability and ability to produce two individual enantiomers of a diarylethane with unambiguously determined absolute configurations and high enantiomeric purities.     

Preparation of 3-(4-chlorophenyl)-2-(2-aminothiazol-4-yl)-5-methoxybenzo[b]furan derivatives and their leukotriene B(4) inhibitory activity

A series of 3-(4-chlorophenyl)-2-(2-aminothiazol-4-yl)benzo[b]furan derivatives 6-10 were prepared and their leukotriene B(4) inhibitory activity was evaluated. We found that several compounds showed strong inhibition of calcium mobilization in CHO cells overexpressing human BLT(1) and BLT(2) receptors. Among them, 3-(4-chlorophenyl)-2-[5-formyl-2-[(dimethylamino)methyleneamino]thiazol-4-yl]-5-methoxybenzo[b]furan 9b showed the most potent and selective inhibition for the human BLT(2) receptor, and its IC(50) value was smaller than that of the selected positive control compound, ZK-158252.     

Total synthesis of 2-(β-D-ribofuranosyl)thiazole-4-carboxamide (Tiazofurin) and of precursors of ribo-C-nucleosides

(1R,2S,4R)-2-Cyano-7-oxabicyclo[2.2.1]hept-5-en-2-yl (1S′)-camphanate ( 5 ) was transformed into (?)-methyl 2,5-anhydro-3,4,6-O-tris[(tert-butyl)dimethylsilyl]-D -allonate ( 2 ), (+)-1,3-diphenyl-2-{2′,3′,5′-O-tris[(tert-butyl)dimethylsilyl]-β-D -ribofuranosyl}imidazolidine ( 3 ), and the benzamide 20 of 1-amino-2,5-anhydro-1-deoxy-3,4,6-O-tris-[((tert-butyl)dimethylsily)]-D -allitol. Compound 2 was converted efficiently into optically active tiazofurin ( 1 ).     

The practical synthesis of a uterine relaxant, bis(2-[[(2S)-2-([(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)-phenyl]ethyl]amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy]-N,N-dimethylacetamide) sulfate (KUR-1246)

The synthetic route for a uterine relaxant, bis(2-[[(2S)-2-([(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)-phenyl]ethyl]amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy]-N,N-dimethylacetamide) sulfate (KUR-1246), was established by the coupling of optically active components, the bromohydrin 14 and the amine 24. We now describe the practical synthesis of these two optically active components. Bromohydrin 14 was obtained by the asymmetric borane reduction of the prochiral phenacyl bromide 13 using a catalyst prepared from aluminum triethoxide and a chiral amino alcohol. The other optically active component 24 was prepared from (S)-AMT.     

Preparation of leukotriene B(4) inhibitory active 2- and 3-(2-aminothiazol-4-yl)benzo[b]furan derivatives and their growth inhibitory activity on human pancreatic cancer cells

A series of 2-(2-aminothiazol-4-yl)benzo[b]furan and 3-(2-aminothiazol-4-yl)benzo[b]furan derivatives were prepared, and their leukotriene B(4) inhibitory activity and growth inhibitory activity in cancer cell lines were evaluated. Several compounds showed strong inhibition of calcium mobilization in CHO cells overexpressing human BLT(1) and BLT(2) receptors and growth inhibition to human pancreatic cancer cells MIA PaCa-2. 3-(4-Chlorophenyl)-2-[5-formyl-2-[(dimethylamino)methyleneamino]thiazol-4-yl]-5-methoxybenzo[b]furan 8b showed the most potent and selective inhibition for the human BLT(2) receptor, and its IC(50) value was smaller than that of the selected positive control compound, ZK-158252. 3-(4-Chlorophenyl)-2-[2-[(dimethylamino)methyleneamino]-5-(2-hydroxyethyliminomethyl)thiazol-4-yl]-5-methoxybenzo[b]furan 9a displayed growth inhibitory activity towards MIA PaCa-2.     

Synthesis,anti-inflammatory and analgesic activity of 2-[4-(substituted benzylideneamino)-5-(substituted phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid derivatives

The title compounds 3a–l have been synthesized by the reaction of thiocarbohydrazide with substituted phenoxy acetic acid to obtained substituted 1,2,4-triazoles (1). Compound 1 was treated with various substituted aromatic aldehydes which results in 4-(substituted benzylideneamino)-5-(substituted phenoxymethyl)-2H-1,2,4-triazol-3(4H)-thiones (2a–g), further 2a–g is converted to 2-[4-(substituted benzylideneamino)-5-(substituted phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid (3a–l) derivatives by the reaction with chloroacetic acid. All the newly synthesized compounds were evaluated for in vivo anti-inflammatory and analgesic activities. Among the series 2-[4-(2,4-dichlorobenzylideneamino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid (3d), 2-[4-(4-dichlorobenzylideneamino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid (3e), 2-[4-(2,4-dichlorobenzylideneamino)-5-[(2,4-dichlorophenoxy)methyl]-4H-1,2,4-triazol-3-yl thio] acetic acid (3j) and 2-[5-[(2,4-dichlorophenoxy)methyl)]-4-(4-chlorobenzylideneamino)-4H-1,2,4-triazol-3-yl thio] acetic acid (3k) showed significant anti-inflammatory activity with P < 0.001 (63.4%, 62.0%, 64.1% and 62.5% edema inhibition, respectively), as compared to the standard drug diclofenac (67.0%) after third hour respectively and also compounds 3j, 3k exhibited significant analgesic activity with P < 0.001 (55.9% and 54.9% protection, respectively) and less ulcerogenic activity as compared with standard drug aspirin (57.8%).