Synthesis and activity of a new series of (Z)-3-phenyl-2-benzoylpropenoic acid derivatives as aldose reductase inhibitors

During the course of studies directed towards the discovery of novel aldose reductase inhibitors for the treatment of diabetic complications, we synthesized a series of new (Z)-3-phenyl-2-benzoylpropenoic acid derivatives and tested their in vitro inhibitory activities on rat lens aldose reductase. Of these compounds, (Z)-3-(3,4-dihydroxyphenyl)-2-(4-methylbenzoyl)propenoicacid (3k) was identified as the most potent inhibitor, with an IC50 of 0.49 microM. The theoretical binding mode of 3k was obtained by simulation of its docking into the active site of the human aldose reductase crystal structure.     

手性2-(2-吡啶基)-4-羧乙基-1,3-噻唑烷的合成及应用研究

以分级结晶和柱层析法对手性配体2-(2-吡啶基)-4-羧乙基-1,3-噻唑烷(A)进行了异构体分离提纯。将其与[Rh(COD)Cl]_2制备的原位催化剂用于催化苯乙酮及其它几种芳香酮的不对称硅氢化反应,化学收率达90％左右,光学纯度达80％e.e.左右,噻唑烷环上的C_2构型对催化反应结果无影响,C_4位上酯基的影响也不大。     

Spectral assignments for the aldose reductase inhibitor 4(S)-2,3-dihydro-6-fluoro-2(R)-methylspiro[chroman-4,4'-imidazoline]-2',5'-dione and its synthetic intermediates

The 1H and 13C NMR chemical shifts of the aldose reductase inhibitor 4(S)-2,3-dihydro-6-fluoro-2(R)-methylspiro[chroman-4,4'-imidazoline]-2',5'-dione, methylsorbinil, and its seven synthetic intermediates, have been completely assigned on the basis of DEPT, COSY, g-HSQC and g-HMBC. All C--F coupling constants from one-bond to four-bond in the 13C NMR spectra and H--F and H--H coupling constants from three-bond to four-bond in 1H spectra were obtained.     

Properties of novel aldose reductase inhibitors, M16209 and M16287, in comparison with known inhibitors, ONO-2235 and sorbinil

Properties and efficacies of novel aldose reductase (AR) inhibitors, M16209 (1-(3-bromobenzo[b]furan-2-ylsulfonyl)hydantoin) and M16287 (1-(3-chlorobenzo[b]furan-2-ylsulfonyl)hydantoin), were examined in vitro and in vivo, compared with known AR inhibitors, ONO-2235 and sorbinil. These four compounds inhibited partially purified aldose reductases from various origins, and the potencies of M16209 and M16287 were on the whole similar to ONO-2235, and were greater than that of sorbinil. The IC50 values of the four AR inhibitors did not substantially depend on the substrate used. Kinetic studies of inhibition of partially purified bovine lens (BLAR) revealed that M16209, M16287 and sorbinil were uncompetitive with glyceraldehyde and noncompetitive with nicotineamide adenine dinucleotide phosphate (NADPH), whereas ONO-2235 was noncompetitive with both glyceraldehyde and NADPH. Aldose reductase became less sensitive to the four inhibitors as enzyme purification progressed, although the susceptibility to inhibition was partially reversed by incubation with dithiothreitol. In addition, the four compounds slightly affected those enzymes of carbohydrate and glutathione metabolism which were tested. M16209 and M16287 prevented sorbitol accumulation in isolated rat tissues as potently as ONO-2235 and sorbinil. M16209 and M16287 were effective in the prevention of galactosemic cataracts and amelioration of diabetic neuropathy with almost the same potency, while ONO-2235 was effective only in neuropathy, and sorbinil was effective in galactosemic cataracts and diabetic neuropathy with a different potency. These results indicate that M16209 and M16287 are potent aldose reductase inhibitors, which could be applicable to treatment for diabetic complications.     

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.     

Improvement of solubility and oral bioavailability of 2-(N-cyanoimino)-5-[(E)-4-styrylbenzylidene]-4-oxothiazolidine (FPFS-410) with antidiabetic and lipid-lowering activities in dogs by 2-hydroxypropyl-beta-cyclodextrin

2-(N-Cyanoimino)-5-[(E)-4-styrylbenzylidene]-4-oxothiazolidine (FPFS-410) is a newly synthesized thiazolidine derivative having not only antidiabetic but also lipid-lowering activities. However, this compound has an extremely low aqueous solubility (2.8 (+/-0.33) x 10(-8) M (0.0094+/-0.0011 microg/ml) in 1.0 M phosphate buffer (pH 7.0) at 25 degrees C). In this study, we investigated the effect of various hydrophilic cyclodextrins (CyDs) on the solubility of FPFS-410 to select a CyD suitable for formulations of the compound. Among various CyDs, 2-hydroxypropyl-beta-CyD (HP-beta-CyD) had the highest solubilizing ability to FPFS-410, e.g., the solubility of the compound was increased 200000-fold by the addition of 40 mM HP-beta-CyD, which was attributable to the formation of the 1 : 2 (guest : host) inclusion complexes. The interaction of HP-beta-CyD with FPFS-410 was studied using 1H-nuclear magnetic resonance (NMR) spectroscopies including ROESY spectroscopy and a molecular modeling calculation. These results suggested that HP-beta-CyD forms a 1:2 (guest : host) inclusion complex with FPFS-410 by including both the stilbene and thiazolidine moieties. FPFS-410/HP-beta-CyD solid complexes with various stoichiometries were prepared by the spray drying and cogrinding methods, and confirmed by powder X-ray diffractometry that these complexes are in an amorphous state. The dissolution of FPFS-410 in water was significantly accelerated by the complexation with HP-beta-CyD. In vivo studies revealed that HP-beta-CyD markedly increases the bioavailability of FPFS-410 after oral administration in dogs. The present results suggest that HP-beta-CyD is useful for improvement of the extremely low bioavailability of FPFS-410.     

2-{2-[3-(取代苯基)-3-氧代-2-1,2,4-三唑-1-基-丙基]-苯基}-2-甲氧亚氨基乙酸甲酯和乙酰甲胺类衍生物的合成与杀菌活性研究

以2-甲基苯甲酰甲酸甲酯为起始原料, 通过与甲氧基胺的盐酸盐、甲胺、N-溴代丁二酰亚胺(NBS)和1H-1,2,4-三氮唑钠反应合成了两个系列共计22个2-{2-[3-(取代苯基)-3-氧代-2-1,2,4-三唑-1-基-丙基]-苯基}-2-甲氧亚氨基乙酸甲酯和乙酰甲胺类的衍生物. 经IR, 1H NMR和MS对目标化合物进行了结构表征. 用浓度为 10 µg•mL－1的目标化合物进行了初步离体杀菌活性试验, 结果表明: Ha4, Ha5, Ha7对油菜菌核病有杀菌活性; Ha2, Hb8对小麦纹枯病有杀菌活性; Hb4对蔬菜灰霉病有杀菌活性; Hb4, Hb5对小麦赤霉病和小麦纹枯病均有杀菌活性.     

Improvement of nerve conduction velocity in mutant diabetic mice by aldose reductase inhibitor without affecting nerve myo-inositol content

The sciatic motor nerve conduction velocity of mutant diabetic C57BL/Ks mice was significantly improved from 30.0 +/- 1.4 to 38.0 +/- 4.6 m/s by treatment with the aldose reductase inhibitor 1-[(beta-naphthyl)sulfonyl]hydantoin (30 mg/kg/d) for 2 weeks. The treatment, however, did not cause any significant change in myo-inositol concentration in the sciatic nerve. The results indicate that the ameliorating effect of the aldose reductase inhibitor on nerve conduction velocity in mutant diabetic mice is not due to alteration of myo-inositol content in the nerve.     

Structural requirements of flavonoids and related compounds for aldose reductase inhibitory activity

The methanolic extracts of several natural medicines and medicinal foodstuffs were found to show an inhibitory effect on rat lens aldose reductase. In most cases, flavonoids were isolated as the active constituents by bioassay-guided separation, and among them, quercitrin (IC(50)=0.15 microM), guaijaverin (0.18 microM), and desmanthin-1 (0.082 microM) exhibited potent inhibitory activity. Desmanthin-1 showed the most potent activity, which was equivalent to that of a commercial synthetic aldose reductase inhibitor, epalrestat (0.072 microM). In order to clarify the structural requirements of flavonoids for aldose reductase inhibitory activity, various flavonoids and related compounds were examined. The results suggested the following structural requirements of flavonoid: 1) the flavones and flavonols having the 7-hydroxyl and/or catechol moiety at the B ring (the 3',4'-dihydroxyl moiety) exhibit the strong activity; 2) the 5-hydroxyl moiety does not affect the activity; 3) the 3-hydroxyl and 7-O-glucosyl moieties reduce the activity; 4) the 2-3 double bond enhances the activity; 5) the flavones and flavonols having the catechol moiety at the B ring exhibit stronger activity than those having the pyrogallol moiety (the 3',4',5'-trihydroxyl moiety).     

手性2-(2-吡啶基)-4-羧乙基-1, 3-噻唑烷的合成及应用研究

以分级结晶和柱层析法对手性配体2-(2-吡啶基)-4-羧乙基-1,3-噻唑烷(A)进行了异构体分离提纯。将其与[Rh(COD)Cl]~2制备的原位催化剂用于催化苯乙酮及其它几种芳香酮的不对称硅氢化反应, 化学收率达90%左右, 光学纯度达80%e.e.左右, 噻唑烷环上的C~2构型对催化反应结果无影响, C~4位上酯基的影响也不大。     

Diastereoisomeric derivatization and liquid chromatographic analysis of N-(phenylsulfonyl)-2-phenylglycine aldose reductase inhibitors

A series of (S)- and (R)-N-(phenylsulfonyl)-2-phenylglycines are synthesized as potential inhibitors of the enzyme aldose reductase. In vitro analysis of these compounds reveals that the S-enantiomers are more potent than the corresponding R-enantiomers and that the difference in potencies between enantiomeric pairs is dependent on the nature of the ring substituent. To ensure that the enantioselectivity observed does not reflect varying degrees of racemization during the synthesis of the N-(phenylsulfonyl)-2-phenylglycines, the enantiomeric purity of these products is determined by HPLC after chiral derivatization. Each 2-phenylglycine inhibitor is derivatized with R-alpha-methylbenzylamine, and the resulting diastereomers are analyzed using reversed and normal achiral stationary phases. Reversed-phase methods with C18 or phenyl stationary phases and solvent mixtures of acetonitrile or methanol in water do not provide satisfactory resolution of the diastereomers. However, normal-phase analyses with a silica stationary phase and mixtures of methanol, ethanol, or acetonitrile in chloroform provide good separations with relatively short analysis times. The normal-phase analyses demonstrate that a single diastereomeric amide forms from each N-(phenylsulfonyl)-2-phenylglycine product, establishing that these compounds do not racemize during synthesis.     

Discovery of a novel and potent human and rat beta3-adrenergic receptor agonist, [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic acid

In search for potent and selective beta3-adrenergic receptor (beta3-AR) agonists as potential drugs for the treatment of type II diabetes and obesity, a novel series of 1-(3-chlorophenyl)-2-aminoethanol derivatives were prepared and evaluated for their biological activity at human beta1-, beta2-, and beta3-ARs and rat beta3-AR expressed in Chinese hamster ovary (CHO) cells. Replacement of the right-hand side (RHS, benzene ring) in the 'first generation' beta3-AR agonists BRL 37344 and CL 316243 with a 1H-indole ring gave compound 31 with unique pharmacological properties among beta3-AR agonists. Initial in vitro assays showed that 31 possesses modest rat and human beta3-ARs agonistic activity. Introduction of various substituent into the indole nucleus of 31 afforded a number of compounds with good beta3-ARs agonistic activity. In particular, 90 having a carboxylic acid functionality at the 7-position of the indole nucleus showed the most potent human beta3-AR agonistic activity. Finally, optical resolution of 90 led to the identification of the most promising compound, [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic acid (96, AJ-9677). This compound exhibited potent human beta3-AR agonistic activity (EC50=0.062 nM, IA=116%) with 210- and 103-fold selectivity over human beta2-AR and beta1-AR, respectively. Compound 96 also exhibited potent rat beta3-AR agonistic activity (EC50=0.016 nM, IA=110%). Moreover, repeated oral administration of 96 inhibited body weight gain and significantly decreased glucose, insulin, free fatty acid, and triglyceride concentrations in plasma in KK-Ay/Ta mice. On the basis of this pharmacological profile, 96 entered clinical development as a drug for the treatment of type II diabetes and obesity.     

Studies on antidiabetic agents. IX. A new aldose reductase inhibitor, AD-5467, and related 1,4-benzoxazine and 1,4-benzothiazine derivatives: synthesis and biological activity

N-Acetic acid derivatives (I) of 2-substituted 1,4-benzoxazines and benzothiazines were designed and synthesized for evaluation as new aldose reductase inhibitors. In general, 3-thioxo derivatives were more potent inhibitors of aldose reductase from human palcenta in vitro than the corresponding 3-oxo derivatives. While many compounds (I) were not very effective in inhibiting sorbitol accumulation in the rat sciatic nerve in vivo, the 3-thioxo compounds bearing an isopropyl group at the 2-position showed highly potent activity in the in vivo assay. Compound 46 (AD-5467) was selected from this series as a candidate for further development.     

Synthesis of 1-(2-Carboxyethylbenzyl)-2-benzenesulfonamidobicyclo[2.2.1]heptane: A Novel Potent Thromboxane Antagonist

A potent thromboxane antagonist, 1-[2-(2-carboxyethyl)benzyl)]-2-benzenesulfonamidobicyclo-[2.2.1]heptane was synthesized from norcamphor in 8 steps. It was shown to be a very potent thromboxane antagonist by inhibition of platelet aggregation induced by U46,619 at nanomolar concentration. The key intermediate 3-[2-bromomethylphenyl]propyl tetrahydropyran ether may be useful for the synthesis of other interphenylene containing prostaglandin analogs.     

Preparation of 2-, 3-, 4- and 7-(2-alkylcarbamoyl-1-alkylvinyl)benzo[b]furans and their BLT1 and/or BLT2 inhibitory activities

Several 2-alkylcarbamoyl-1-alkylvinylbenzo[b]furans were designed to find a selective leukotriene B4 (LTB4) receptor antagonist. 2-(2-Alkylcarbamoyl-1-alkylvinyl)benzo[b]furans having a substituent group at the 3-position, 4-(2-alkylcarbamoyl-1-methylvinyl)benzo[b]furans having a substituent group at the 3-position, and 7-(2-alkylcarbamoyl-1-methylvinyl)benzo[b]furans and 3-(2-alkylcarbamoyl-1-alkylvinyl)benzo[b]furans were prepared and evaluated for LTB4 receptor (BLT1 and BLT2) inhibitory activities. (E)-3-Amino-4-[2-[2-(3,4-dimethoxyphenyl)ethylcarbamoyl]-1-methylvinyl]benzo[b]furan ((E)-17c) showed potent and selective inhibitory activity for BLT2. On the other hand, (E)-7-(2-diethylcarbamoyl-1-methylvinyl)benzo[b]furan ((E)-27a) showed potent inhibitory activity for both BLT1 and BLT2.     

2-(O-Phenylalkyl)phenoxy]alkylamines III: Synthesis and selective serotonin-2 receptor binding (2)

A series of 12-(2-phenylethyl)phenoxy]ethylpyrrolidine derivatives were synthesized, and their affinity for serotonin-2 (5-HT2) and dopamine-2 (D2) receptors was examined. Among them, compound 17, (2R,4R)-4-hydroxy-2-[2-[2-[2-(3-methoxyphenyl)ethyl]phenoxylethyl] -1-methylpyrrolidine hydrochloride, showed high 5-HT2 receptor affinity in vitro. This compound was a more potent inhibitor of ex vivo 5-HT-induced platelet aggregation than compound 3, which was previously shown to be more potent than ketanserin (1) and sarpogrelate (2a). However, compound 17 produced gastric irritation in rats. Therefore, we carried out a further derivatization of 17, and compound 45 (R-102444), a lauryl ester prodrug of compound 17, was found to be a promising candidate as an antithrombotic agent. Oral administration of R-102444 produced a marked inhibition of 5-HT-induced ex vivo platelet aggregation, and R-102444 did not cause any gastric irritation. The antiaggregatory effects of R-102444 were more potent than those of sarpogrelate (2a) and its active metabolite, M-1 (2b). In addition, R-102444 exhibited more potent antithrombotic effects than sarpogrelate in a rat photochemically-induced thrombosis model.     

A novel method for the synthesis of 9-[[2-hydroxy-1-(aminomethyl)ethoxy]methyl]guanine - a potential antiviral agent

9-[[2-Hydroxy-1-(aminomethyl)ethoxy]methyl]guanine (1a), an amino analogue of 9-[[2-hydroxy-1-(hydroxymethyl)-ethoxy]methyl]guanine (I) which is a potent antiviral agent, has been synthesized $\text{via}$ a multistep-synthesis.     

The coordination chemistry of thiazoline/thiazolidine derivatives. II: synthesis and characterization of [CoCl2(PyTT)] and [ZnCl2(PyTT)] [PyTT=2-(2-pyridyl)imino-N-(2-thiazolin-2-yl)thiazolidine]

The compounds dichloro[2-(2-pyridyl)imino-κN---N-(2-thiazolin-κN-2-yl)thiazolidine]cobalt(II) and dichloro[2-(2-pyridyl)imino-κN---N-(2-thiazolin-κN-2-yl)thiazolidine]zinc(II) have been isolated and characterized by single crystal X-ray diffraction and IR spectroscopy. Moreover, the cobalt(II) complex has been studied by means of magnetic susceptibility measurements and UV–Vis–NIR diffuse reflectance. Both complexes are isostructural. The environment around the cobalt(II) and zinc(II) atoms may be described as a distorted tetrahedral geometry with the metallic atoms coordinated to two chlorine atoms [Co---Cl(1)=2.241(1) Å; Co---Cl(2)=2.221(1) Å], [Zn---Cl(1)=2.235(1) Å; Zn---Cl(2)=2.211(1) Å], one thiazoline nitrogen [Co---N(1)=1.982(2) Å], [Zn---N(1)=2.021(2) Å] and one imino nitrogen [Co---N(3)=2.009(1) Å], [Zn---N(3)=2.056(2) Å].     

Synthesis and antiestrogenic activity of the compounds related to the metabolites of (E)-4-[1-[4-[2-(dimethylamino)ethoxy]phenyl]- 2-(4-isopropylphenyl)-1-butenyl]phenyl monophosphate (TAT-59) [corrected

The metabolites of (E) [corrected]-4-[1-[4-[2-dimethylamino)ethoxy]phenyl]- 2-(4-isopropylphenyl)-1-butenyl]phenyl monophosphate, TAT-59, (1), a potent antitumor agent for hormone-dependent tumors, and derivatives of TAT-59 were synthesized to confirm its proposed structure. The structure and the Z-configuration of the metabolites (2a-8a) were confirmed by comparison with synthesized authentic compounds. All of the metabolites and the derivatives of TAT-59 were tested for a binding affinity toward estrogenic receptors in vitro and antiuterotrophic activity in vivo. Most of the metabolites possessed remarkable binding affinity toward estrogenic receptors as well as fairly good antiuterotrophic activity.     

HPLC determination of acetaminophen in saliva based on precolumn fluorescence derivatization with 12-(3,5-dichloro-2,4,6-triazinyl)benzo[d]benzo[1',2'-6,5]isoindolo[1,2-b][1,3]thiazolidine.

A high-performance liquid-chromatographic method for the determination of acetaminophen in saliva has been developed. This method is based on the precolumn derivatization of acetaminophen with 12-(3,5-dichloro-2,4,6-triazinyl)benzo[d]benzo[1',2'-6,5]isoindolo[1,2-b][1,3]thiazolidine, a new fluorescence derivatization reagent for phenolic compounds. The resulting derivative of acetaminophen is separated by isocratic elution on a reversed-phase column, and is fluorometrically detected at an emission wavelength of 560 nm with an excitation wavelength of 540 nm. The detection limit (signal-to-noise ratio = 3) was 0.1 microg/mL in saliva. The proposed method permits a highly sensitive and simple determination of acetaminophen in a small amount of saliva without any sample purification.