Language：English   Publisher：WILEY-BLACKWELL  

The reaction of the 4-hydroxyquinoline-3-carboxylate 6 with pentaerythritol tribromide gave the 1,1-(2-methylenepropane-1,3-diyl)di(4-quinolone-3-carboxylate) 11, whose reaction with bromine afforded the 1,1-(2-bromo-2-bromomethylpropane-1,3-diyl)di(4-quinolone-3-carboxylate) 12. Compound 12 was transformed into the (Z)-1,1-(2-acetoxymethylpropene-1,3-diyl)di(4-quinolone-3-carboxylate) 13 or (E)-1,1-[2-(imidazol-1-ylmethyl)propene-1,3-diyl]di(4-quinolone-3-carboxylate) 14. Hydrolysis of the dimer (Z)-13 or (E)-14 with potassium hydroxide provided the (E)-1,1-(2-hydroxymethylpropene-1,3-diyl)di(4-quinolone-3-carboxylic acid) 15 or (Z)-1,1-[2-(imidazol-1-ylmethyl)propene-1,3-diyl]di(4-quinolone-3-carboxylic acid) 16, respectively. The nuclear Overhauser effect (NOE) spectral data supported that those hydrolysis resulted in the geometrical conversion of (Z)-13 into (E)-15 or (E)-14 into (Z)-16.

DOI： 10.1002/jhet.1861

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The 1-hydrazinocarbonylmethyl-4-quinolone-3-carboxylate (10) was converted into the 1-(4-amino-1,2,4-triazol-3-ylmethyl)-4-quinolone-3-carboxylic acid (13), whose reaction with arylcarbaldehydes gave the 1-(4-arylmethyleneamino-1,2,4-triazol-3-ylmethyl)-4-quinolone-3-carboxylic acids (5a, 5b, 5c, 5d, 5e, 5f, 5g). Compound 10 was also transformed into the 1-(4-amino-1,2,4-triazol-3-ylmethyl)-4-quinolone-3-carbohydrazide (15), whose reaction with phenyl isocyanate or phenyl isothiocyanate afforded the 4-phenyl-1-(1-triazolylmethyl-4-quinolon-3-ylcarbonyl)semicarbazide (6a) or 4-phenyl-1-(1-triazolylmethyl-4-quinolon-3-ylcarbonyl)thiosemicarbazide (6b), respectively. Compounds 6a, 6b showed the in vitro antimalarial activity to chloroquine-resistant Plasmodium falciparum, wherein their IC50 was 3.89 and 3.91 mu M, respectively.

DOI： 10.1002/jhet.1822

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Reaction of 3-(3-cyanopropylthio)[1]benzothiophene-2-carbonitrile with tert-BuONa gave 5-amino-1,2-dihydro[1]benzothieno[3,2-d]thieno[2,3-b]pyridine and 5-amino-2,3-dihydro[1]benzothieno[3,2-b]thiepin-4-carbonitrile. The latter compound served as a convenient scaffold for the synthesis of the new heterocycles, [1]benzothieno[3,2:2,3]thiepino[4,5-d]pyrimidines. All of our new tetracyclic products were evaluated for in vitro inhibitory activity on the formation of pentosidine, which is one of representative advanced glycation end products.

DOI： 10.1002/jhet.1709

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We have synthesized a large number of tricyclic 2-substituted 4-alkylamino-5,6-dihydro[1]benzothiepino[5,4-d]pyrimidines as part of our research to develop new effective anti-platelet drugs. A variety of alkyl and aryl groups were used as substituents at the 2-position. Evaluation of the effects of the newly synthesized compounds on collagen-induced platelet aggregation revealed several promising anti-platelet candidates with potencies superior to aspirin.

DOI： 10.1002/jhet.1741

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Libraries of tricyclic 2-substituted 4-alkylamino-5,6-dihydro[1]benzoxepino[5,4-d]pyrimidines and tetracyclic 12-substituted 1,2,4,5-tetrahydro[1]benzoxepino[4,5-e]imidazo[1,2-c]pyrimidines were synthesized as part of our research to develop new effective antiplatelet drugs. Several alkyl and aryl groups were used as substituents at the 2-position. Evaluation of the effects of the newly synthesized compounds on collagen-induced platelet aggregation revealed several promising antiplatelet candidates with potencies superior to aspirin.

DOI： 10.1002/jhet.1559

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Treatment of 2-substituted 4-chloro-5,6-dihydro[1]benzofuro[3',2':2,3]oxepino[4,5-d]pyrimidines with simple alcohols and thiols as nucleophile afforded 2-substituted 4-alkoxy (or sulfanyl) derivatives. In the case of alkoxide nucleophiles, rearranged reaction products were also obtained. X-ray crystallography was used to support the structure assignment of the rearranged product.

DOI： 10.1002/jhet.1900

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Reaction of several Vilsmeier reagents with 5-amino-2,3-dihydro[1]benzofuro[3,2-b]oxepin-4-carbonitrile gave tetracyclic 2-substituted 4-chloro-5,6-dihydro[1] benzofuro[3',2':2,3]oxepino[4,5-d]pyrimidines. The structure of one of these, the 4-chloro-2-phenyl derivative, was confirmed by X-ray crystallography. Treatment of the 4-chloro derivatives with simple amines as nucleophile afforded 2-substituted 4-amino derivatives. A pentacyclic compound was also obtained by dehydrative ring closure. These products were evaluated for antiplatelet activity, and some showed potency comparable with that of aspirin.

DOI： 10.1002/jhet.1539

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N-[2-([1,2,4]Oxadiazol-5-yl)cyclohepten-1-yl]formamide oximes were synthesized by fusion of (6,7,8,9-tetrahydro-5H-cyclohepta[1,2-d]pyrimidin-4-yl)amidines with hydroxylamine hydrochloride through a subsequent rearrangement reaction. Effects of the products as well as the structurally related N-[4-([1,2,4]oxadiazol-5-yl)-2,3-dihydro[1]benzoxepin-5-yl]formamide oximes and N-[4-([1,2,4]oxadiazol-5-yl)-2,3-dihydro[1]benzothiepin-5-yl]formamide oximes on platelet aggregation were evaluated.

DOI： 10.1002/jhet.1628

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Reaction of 3-(3-cyanopropoxy)[1]benzothiophene-2-carbonitrile with sodium hydride gave 5-amino-1,2-dihydro[1]benzothieno[3,2-d]furo[2,3-b]pyridine and 5-amino-2,3-dihydro[1]benzothieno[3,2-b]oxepin-4-carbonitrile. The latter compound served as a convenient scaffold for the synthesis of the new heterocycles [1]benzothieno[3,2:2,3]oxepino[4,5-d]pyrimidines and the parent 1,2,4,5-tetrahydro[1]benzothieno[2,3:6,7]oxepino[4,5-e]imidazo[1,2-c]pyrimidine heterocyclic system. The new compounds described in this report were evaluated as inhibitors of platelet aggregation in vitro.

DOI： 10.1080/00397911.2012.656295

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Several 5-substituted 1,2-dihydro[2,3-c]isoquinoline derivatives were synthesized as part of our research to develop new diabetes drugs. Amines and sulfanyls were used as substituents at the 5th-position. Evaluation of the effects of the newly synthesized compounds on lipoprotein lipase mRNA expression in 3T3-L1 preadipocytes revealed one promising candidate with potency comparable to that of troglitazone.

DOI： 10.1002/jhet.1016

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Language：English   Publisher：Bentham Science Publishers B.V.  

Each year in the United States, at least 2 million people become infected with bacteria that are resistant to antibiotics and at least 23,000 people die each year as a direct result of these infections (Threat report 2013). Vancomycin is an FDA approved antibiotic and is growing importance in the treatment of hospital infections, with particular emphasis on its value to fight against methicillin-resistant Staphylococcus aureus (MRSA). The increasing use of vancomycin to treat infections caused by the Gram-positive MRSA in the 1970s selected for drug-resistant enterococci, less potent than staphylococci but opportunistic in the space vacated by other bacteria and in patients with compromised immune systems. The dramatic rise of antibiotic-resistant bacteria over the past two decades has stressed the need for completely novel classes of antibacterial agents. This paper reports the recent patent review on the strategy for finding novel quercetinglycoside type antibacterial agents against vancomycin-resistant bacterial strains. © 2013 Bentham Science Publishers.

DOI： 10.2174/1574891X08666131210124649

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The 4-quinolone-2-carboxylates 4a,b were converted into the 4-quinolone-2-carbohydrazides 5a,b, hydrazones 6,7,10, and related compounds 8,9,11. The 4-methoxyquinoline-2-carboxylate 12 was also transformed into the 4-methoxyquinoline-2-carbohydrazide 13, which was modified to the hydrazone 14 and related compound 15. The antimicrobial activities of compounds 6b and 14 are described together with the 4-oxo and 4-hydroxy tautomers of compounds 4-11 in deuteriodimethyl sulfoxide and deuteriotrifluoroacetic acid.

DOI： 10.1002/jhet.922

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Several 5-substituted 1,2-dihydrofuro[3,2-f][1,7]naphthyridines were synthesized as part of our research to develop new effective bronchodilators. Amines, sulfanyls, and alcohols were used as substituents at the fifth position. Tetracyclic compounds were also obtained. Evaluation of the effects of the newly synthesized compounds on carbamoylcholine chloride-induced contractions of trachea revealed one promising bronchodilator candidate with potency comparable to that of 3-isobutyl-1-methylxanthine.

DOI： 10.1002/jhet.846

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

We synthesized calothrixin B using our developed biomimetic method and derived N-alkyl-calothrixins A and B. The in vitro antimalarial activity of the calothrixin derivatives, including calothrixins A and B, against the Plasmodium falciparum FCR-3 strain was evaluated. All test compounds exhibited antimalarial activity over a concentration range of 6.4 x 10(-6)-1.2 x 10(-7) M. (C) 2012 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2012.05.064

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Reaction of 3-(3-cyanopropoxy)[1]benzofuran-2-carbonitriles with potassium tert-butoxide gave 5-amino-1,2-dihydro[1]benzofuro[3,2-d]furo[2,3-b]pyridines and 5-amino-2,3-dihydro[1]benzofuro[3,2-b]oxepin-4-carbonitriles as new ring systems. Reactions of the 5-chloro derivative, obtained from 5-amino-1,2-dihydro[1]benzofuro[3,2-d]furo[2,3-b]pyridine, produced a dihydrofuran ring-opened compound and 5-substituted compounds. J. Heterocyclic Chem.,(2011).

DOI： 10.1002/jhet.772

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Language：English   Publisher：TAYLOR & FRANCIS INC  

Reaction of 5-amino-1,2-dihydrofuro[2,3-c]isoquinolines with 1,2-dibromoethane and 1,3-dibromopropane in the presence of a base afforded 2',3'-dihydrospiro[cyclopropane-1,6'(5'H)-imidazo[2,1-a]isoquinolin]-5'-ones land 3',4'-dihydro-2'H-spiro[cyclopropane-1,7'(6'H)-pyrimido[2,1-a]isoquinolin]-6'-ones, respectively. Certain of the products showed significant bronchodilator activity.

DOI： 10.1080/00397911.2010.532899

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Language：English   Publisher：AMER CHEMICAL SOC  

A structure-guided molecular design approach was used to optimize quercetin diacylglycoside analogues that inhibit bacterial DNA gyrase and topoisomerase IV and show potent antibacterial activity against a wide spectrum of relevant pathogens responsible for hospital- and community-acquired infections. In this paper, such novel 3,7-diacylquercetin, quercetin 6 ''-acylgalactoside, and quercetin 2 '',6 ''-diacylgalactoside analogues of lead compound 1 were prepared to assess their target specificities and preferences in bacteria. The significant enzymatic inhibition of both Escherichia coli DNA gyrase and Staphylococcus aureus topoIV suggest that these compounds are dual inhibitors. Most of the investigated compounds exhibited pronounced inhibition with MIC values ranging from 0.13 to 128 mu g/mL toward the growth of multidrug-resistant Gram-positive methicillin-resistant S. aureus, methicillin sensitive S. aureus, vancomycin-resistant enterococci (VRE), vancomycin intermediate S. aureus, and Streptococcus pneumoniae bacterial strains. Structure activity relationship studies revealed that the acyl moiety was absolutely essential for activity against Gram-positive organisms. The most active compound 5i was 512-fold more potent than vancomycin and 16-32-fold more potent than 1 against VRE strains. It also has realistic in situ intestinal absorption in rats and showed very low acute toxicity in mice. So far, this compound can be regarded as a leading antibacterial agent.

DOI： 10.1021/jm200010x

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Reaction of 3-(3-cyanopropoxy)thieno[2,3-b]pyridine-2-carbonitriles with potassium tert-butoxide gave 5-amino-1,2-dihydrofuro[2,3-b]pyrido[3',2':4,5]thieno[3,2-d]pyridines via a Truce-Smiles rearrangement. The 5-amino group was transformed to the chloro derivatives which were allowed to react with various nucleophiles. Effects of the newly synthesized compounds on lipoprotein lipase mRNA expression were also evaluated. The previously unreported parent compound, furo[2,3-b]pyrido[3',2':4,5]thieno[3,2-d]pyridine, was also synthesized.

DOI： 10.3987/COM-11-12187

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N-[2-([1,2,4]Oxadiazol-5-yl)cyclopenten-1-yl]formamide oximes were synthesized by fusion of (6,7-dihydro-5H-cyclopenta[1,2-d]pyrimidin-4-yl)amidines and/or their amide oximes with hydroxylamine hydrochloride through a subsequent rearrangement reaction. Assay of the products for anti-platelet aggregation activity revealed that certain of them showed promising inhibitory effect on arachidonic acid-induced platelet aggregation.

DOI： 10.1002/jhet.564

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[image omitted] The reaction of 3-(2-bromoethyl)quinazolin-4(3H)-one with ethyl- and n-propylamine gave abnormal fused 3-alkyl-4-alkyliminoquinazolines via a Dimroth-type rearrangement, as well as normal substituted 3-(2-alkylaminoethyl) derivatives in methanol. The reaction of 3-(2-bromoethyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one with primary alkylamines was also investigated for the scope of this rearrangement reaction.

DOI： 10.1080/00397911003668570

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In the title compound, C11H9ClN2O, the fused-ring system is essentially planar, with a maximum deviation of 0.0323 (16) angstrom. In the crystal, molecules are connected by N-H center dot center dot center dot O hydrogen bonds forming a zigzag chain along the c axis. Molecules are further stacked along the a axis through weak pi-pi interactions, the shortest being 3.6476 (8) angstrom.

DOI： 10.1107/S160053681004273X

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A series of novel quercetin diacylglucosides were designed and first synthesized by Steglich esterification on the basis of MRSA strains inhibiting natural compound A. The in vitro inhibition of different multidrug resistant bacterial strains and Escherichia coli DNA gyrase B was investigated. In the series, compound 10h was up to 128-fold more potent against vancomycin-resistant enterococci and more effective than A, which represents a promising new candidate as a potent anti-MRSA and anti-VRE agent. (C) 2010 Published by Elsevier Ltd.

DOI： 10.1016/j.bmcl.2010.02.060

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Language：English   Publisher：PHARMACEUTICAL SOC JAPAN  

Reaction of 1-(3-cyanopropoxy)-3,4-dihydronaphthalene-2-carbonitriles with potassium tert-butoxide gave 5-amino-1,2,6,7-tetrahydrobenzo[f]furo[2,3-c]isoquinolines via a Truce Smiles rearrangement. The 5-amino group was transformed to the bromo derivatives which were allowed to react with aliphatic cyclic amines to produce amino derivatives. In contrast, a combination of imidazole and NaH gave a dihydrofuran ring cleaved product, the structure of which was confirmed by X-ray crystallographic analysis. Effects of the newly synthesized compounds on carbamylcholine chloride-induced contractions of trachea and lipoprotein lipase mRNA expression were also evaluated and found one promising bronchodilator.

DOI： 10.1248/cpb.58.685

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Language：English   Publisher：PHARMACEUTICAL SOC JAPAN  

Reaction of fused 2,3-dihydrofuro[2,3-b]pyridines with various nucleophiles (N and O) gave dihydrofuran ring cleaved products. The scope of this reaction was investigated in detail.

DOI： 10.1248/cpb.58.755

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An improved synthesis of 5-amino-1,2-dihydrofuro[2,3-c]isoquinoline has been achieved using a slight niodification of reaction Conditions for the Truce-Smiles rearrangement. Acid treatment of the obtained 5-amino-1,2-dihydrofuro [2,3-c]isoquinolines gave unexpected ring-opened spiro ring compounds. The previously unreported Parent compound, furo[2,3-c]isoquinoline, was also synthesized.

DOI： 10.1248/cpb.58.363

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Language：English   Publisher：PHARMACEUTICAL SOC JAPAN  

The reactions of N-(5,6,7,8-tetrahydroquinazolin-4-yl)amidines and their amide oximes with hydroxylamine hydrochloride gave abnormal cyclization products via a ring cleavage of pyrimidine component accompanied with a ring closure of 1,2,4-oxadiazole to give N-[2-([1,2,4]oxidiazol-5-yl)cyclohexen-1-yl]formamide oximes. Similarly, N-(quinazolin-4-yl)amidines reacted with hydroxylamine hydrochloride gave the same results. The evaluation of inhibitory activities against platelet aggregation in vitro is also described to show one derivative has potent activity.

DOI： 10.1248/cpb.58.369

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The cycloalkeno[1,2-d]furo[2,3-b]pyridine skeleton was conveniently synthesized from fused 4-(2-cyanovinyloxy)butanenitriles in one step through sequential intramolecular Michael addition, p-elimination and intramolecular nucleophilic addition. This sequence thus consists of a novel Truce-Smiles type rearrangement followed by cyclization. The 5-amino derivatives were transformed further to lactams in good yields. (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2009.12.010

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The reaction of 3-(2-cyanophenyl)quinazolin-4(3H)-one with various primary alkylamines gave 3-alkylquinazolin-4(3H)-ones via an addition of the nucleophile, ring opening, and ring closure (ANRORC) mechanism. This type of reaction required hydroxy group functionality in either the solvent or reagent. When hydroxylamine was used as nitrogen nucleophile, the intermediate of this reaction was isolated and found to be an amide oxime. When ethylenediamine was used as the lie nucleophile, the amidine moiety of the intermediate decomposed to give a benzanilide.

DOI： 10.1248/cpb.57.1296

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Reaction of some fused tricyclic 3-(2-bromoethvl)pyrimidin-4(3H)-ones with primary alkyl amines gave abnormal fused 3-alkyl-4-alkyliminopyrimidines via a Dimroth-type rearrangement, as well as normal substituted 3-(2-alkylaminoethyl) derivatives in methanol. This abnormal rearrangement reaction depended on reaction solvent.

DOI： 10.1248/cpb.57.755

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Retinoid X receptor (RXR) ligands are attractive candidates for clinical application because of their activity against tamoxifen-resistant breast cancer, taxol-resistant lung cancer, metabolic syndrome, and allergy. Though several RXR ligands, especially RXR antagonists, have been reported, the rational molecular design of such compounds is not well advanced. 4-[N-Methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) amino] nicotinic acid (5a) is a moderately RXR alpha-preferential agonist, and we examined the feasibility of replacing the methyl group on the sulfonamide with a longer alkyl chain or an aromatic ring as an approach to produce new RXR antagonists. Several of the resulting benzenesulfonanilide-type compounds showed RXR antagonist activity. This design strategy should be a useful approach for addressing the lack of structure diversity of RXR antagonists. (C) 2008 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2008.11.086

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Language：English   Publisher：JOHN WILEY & SONS INC  

A benzensulfonanilide-type cyclooxygenase-1 (COX-1)-selective inhibitor, ZXX2-77: 4-amino-4'-chloro-N-methylbenzenesulfonanilide (4a), has been reported as a novel analgesic that does not cause gastric damage. This compound has a weak analgesic effect but has potent in vitro COX-1 inhibitory activity. Since the reason for the weak analgesic effect in vivo was thought to be the low rate of oral absorption, the blood concentration of ZXX2-77 (4a) was measured in rats. It was found that the C(max) value (1.2 mu M) of ZXX2-77 (4a) at a dose of 30 mg/kg did not reach the COX-1 IC(50) value (3.2 mu M). On the other hand, ZXX2-79 (4b) (SO(2)NH derivative of ZXX2-77 (4a); 4-amino-4'-chlorobenzenesulfonanilide), which shows less potent COX inhibitory activities (COX-1 IC(50) = 12 mu M, COX-2 IC(50) = 150 mu M) than those of ZXX2-77 (4a) in vitro, was found to be more absorbable (C(max) - 16 mu M at a dose of 30 mg/kg in rats) than ZXX2-77 (4a). Furthermore, ZXX2-79 (4b) not only showed a potent analgesic effect in a formalin test but also caused little gastric damage. These findings indicate that demethylated sulfonamide compounds are more easily absorbed than are N-methylated sulfonamide compounds and suggest that COX-1-selective inhibitors will be useful as analgesics that do not cause gastric damage. (C) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5446-5452, 2008

DOI： 10.1002/jps.21388

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Malaria is a leading cause of death in developing countries, and the emergence of strains resistant to the main therapeutic agent, chloroquine, has become a serious problem. We have developed cationic-dimer type antimalarials, MAP-610 and PMAP-H10, which are structurally different from chloroquine. In this study, we introduced several substituents on the terminal phenyl rings of PMAP-H10. The electronic and hydrophobic properties of the substituents were correlated with the antimalarial activity and cytotoxicity of the compounds, respectively. Studies with synchronized cultures of malarial plasmodia showed that our cationic-dimers act selectively between the schizont stage and the ring stage of the parasitic cycle, unlike chloroquine, which has a stage-independent action. Thus, the mechanism of action of our antimalarials appears to be different from that of chloroquine, and our compounds may be effective against chloroquine-resistant strains. (C) 2008 Published by Elsevier Ltd.

DOI： 10.1016/j.bmc.2008.04.051

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Vancomycin is mainly used as an antibacterial agent of last resort, but recently vancomycin-resistant bacterial strains have been emerging. Although new antimicrobials have been developed in order to overcome drug-resistant bacteria, many are structurally complex beta-lactams or quinolones. In this study, we aimed to create new anti-drug-resistance antibacterials which can be synthesized in a few steps from inexpensive starting materials. Since sulfa drugs function as p-aminobenzoic acid mimics and inhibit dihydropteroate synthase (DHPS) in the folate pathway, we hypothesized that sulfa derivatives would act as folate metabolite-mimics and inhibit bacterial folate metabolism. Screening of our sulfonanilide libraries, including benzenesulfonanilide-type cyclooxygenase-1-selective inhibitors, led us to discover benzenesulfonanilides with potent anti-methicillin-resistant Staphylococcus aureus (MRSA)/vancomycin-resistant Enterococcus (VRE) activity, that is, N-3,5-bis(trifluoromethyl) phenyl-3,5-dichlorobenzenesulfonanilide (16b) [MIC = 0.5 mu g/mL (MRSA), 1.0 mu g/mL (VRE)], and 3,5-bis(trifluoromethyl)-N-(3,5-dichlorophenyl) benzenesulfonanilide (16c) [MIC = 0.5 mu g/mL (MRSA), 1.0 mu g/mL (VRE)]. These compounds are more active than vancomycin [MIC = 2.0 mu g/mL (MRSA), 125 mu g/mL (VRE)], but do not possess an amino group, which is essential for DHPS inhibition by sulfa drugs. These results suggested that the mechanism of antibacterial action of compounds 16b and 16c is different from that of sulfa drugs. We also confirmed the activity of these compounds against clinical isolates of Gram-positive bacteria. (C) 2008 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmc.2008.04.040

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Retinoid X receptor (RXR) agonists (rexinoids) ore attracting much attention for their use in treatment of cancers, including tomoxifen-resistant breast cancer and toxol-resistant lung cancer, and metabolic disease. However, known RXR agonists have a highly lipophilic character. In addition, no subtype-selective RXR agonists have been found. We previously reported on RXR alpha-preferential agonist 4-[N-methanesulfonyl-N-(5,5,8,8-tetromethyl-5,6,7,8tetrahydro-2-naphthyl)amino]benzoic acid (6a). The RXR agonistic activity is much less than that of well-known RXR agonists. To develop potent, less-lipophilic, and subtype-selective RXR agonists, we created new RXR agonists possessing alkoxy and isopropyl groups as a lipophilic domain of the common structure of well-known RXR agonists. As a result, compounds possessing branched alkoxy groups, 6-[N-ethyl-N-(3-isopropoxy-4-isopropylphenyl)amino]nicotinic acid (NEt-3IP: 7a) and 6-[N-ethyl-N-(3-isobutoxy-4-isopropylphenyl)amino]nicotinic acid (NEt-3IB: 7c), showed RXR agonistic activity as potent as, or more potent than, the activities of representative RXR agonists. Moreover NEt-3IP (7a) was found to be the first RXR alpha/beta-selective (or RXR alpha/beta-dual) agonist. Being potent, less lipophilic, and having RXR subtype-selective activity, NEt-3IP (7a) is expected to become a new drug candidate and to be a useful biological toot for clarifying each RXR subtype function.

DOI： 10.1002/cmdc.200700313

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Although cyclooxygenase-1 (COX-1) inhibition is thought to be a major mechanism of gastric damage by nonsteroidal anti-inflammatory drugs (NSAIDs), some COX-1-selective inhibitors exhibit strong analgesic effects without causing gastric damage. However, it is not clear whether their analgesic effects are attributable to COX-1-inhibitory activity or other bioactivities. Here, we report that N-(5-amino-2-pyridinyl)-4(trifluoromethyl)benzamide (18f, TFAP), which has a structure clearly different from those of currently available COX-1-selective inhibitors, is a potent COX-1-selective inhibitor (COX-1IC(50) = 0.80 +/- 0.05 mu M, COX-2IC(50) = 210 I mu M). This compound causes little gastric damage in rats even at an oral dose of 300 mg/kg, though it has an analgesic effect at as low a dose as 10 mg/kg. Our results show that COX-1-selective inhibitors can be analgesic agents without causing gastric damage.

DOI： 10.1021/jm701191z

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Language：English   Publisher：WILEY-V C H VERLAG GMBH  

Retinoid X receptor agonists (RXR agonists, rexinoids) are interesting candidates for the treatment of cancers such as tomoxifen-resistant breast cancer and taxol-resistant lung cancer. However, well-known RXR agonists possess a strong lipophilic character. In addition, although RXR has three subtypes, no subtype-selective RXR agonists are known. Thus we aimed to produce less-lipophilic and subtype-selective RXR agonists. By designing sulfonamide-type RXR agonists, 4-[N-methanesulfonyl-N-(5,5,8,8-tetromethyl-5,6,7,8-tetrohydro-2-naphthyl)amino]benzoic acid (80) was found to prefer RXR alpha over RXR beta and RXR gamma, although the potency is less than the potencies of well-known RXR pan-agonists. Moreover, our results suggest that the reduction of lipophilicity at the hydrophobic interaction region of RXR agonists enables production of RXR subtype preference. Our finding will be useful for the creation of more potent and less-lipophilic subtype-selective RXR agonists aimed at the reduction of undesirable side effects.

DOI： 10.1002/cmdc.200700265

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Reaction of fused 3-(2-bromoethyl)pyrimidin-4(3H)-ones with primary alkylamines gave abnormal fused 3-alkyl-4-alkylimino-pyrimidines via a new rearrangement, as well as normal substituted 3-(2-alkylaminoethyl) derivatives. Antidepressive evaluation of these compounds was performed by antireserpine action and one compound exhibited the positive activity comparable to imipramine. (c) 2007 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2007.10.024

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Language：English   Publisher：WILEY-V C H VERLAG GMBH  

Malaria is one of the three major serious infectious diseases in the world. As the area affected by malaria includes a large proportion of developing countries, there is a need for new antimalarials that can be synthesized and supplied inexpensively. To generate low-cost antimalarials, the MAP series 6-10, bis-cation dimers, synthesized by amidating the carboxyl group of isonicotinic acid (11) with various amines and by cationizing the nitrogen atoms of the pyridine ring with the corresponding alkyl bromides, were designed. This design enabled expansion of the structural variations of bis-cation-type antimalarial compounds. The compounds bearing alkyl or phenyl groups in the amide moieties showed remarkable antimalarial activities in vitro. Moreover, 1, 1'-(1, 12-dodecanediyl)bis[4-[(buthylamino)carbonyl]pyridinium bromide], MAP-412 (6d), exhibited a potent antimalarial activity (ED50 = 8.2 mg kg-(1)). Being prepared at low cost our biscation-type antimalarial compounds may be useful as lead compounds for inexpensive antimalarials.

DOI： 10.1002/cmdc.200700107

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

In order to create novel analgesic agents without gastric disturbance, structurally simple cyclooxygenase-1 (COX-1) inhibitors with a benzenesulfonanilide skeleton were designed and synthesized. As a result, compounds 11f and 15a, which possess a p-amino group on the benzenesulfonyl moiety and p-chloro group on the anilino moiety, showed COX-1-selective inhibition. Moreover compound 11f, which is the most potent compound in this study showed more potent analgesic activity than that of aspirin at 30 mg/kg by po. The anti-inflammatory activity and gastric damage, however, were very weak or not detectably different from aspirin. Since the structure of our COX-1 inhibitors are very simple, they may be useful as lead compounds for superior COX-1 inhibitors as analgesic agents without gastric disturbance. (c) 2006 Published by Elsevier Ltd.

DOI： 10.1016/j.bmc.2006.10.029

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The in vitro antimalarial activity of bis-pyridinium salts, N,N'-hexamethylenebis(4-carbamoyl-1-decylpyridinium bromide) and their derivatives, against the Plasmodium falciparum FCR-3 strain (ATCC 30932, chloroquine-sensitive) was evaluated. All test compounds exhibited antimalarial activity over a concentration range of 3.5 mu M to 10 nM. The chain length of the N1-alkyl moiety was found to be very beneficial in terms of antimalarial activity, and in this series of compounds, the most appropriate N1-alkyl chain length was found to be eight. (C) 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2006.02.030

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We recently reported that nonsteroidal anti-inflammatory drug (NSAIB)-induced gastric lesions involve NSAID-induced apoptosis of gastric mucosal cells, which in turn involves the endoplasmic reticulum stress response, in particular the up-regulation of CCAAT/enhancer-binding protein homologous transcription factor (CHOP). In this study, we have examined the molecular mechanism governing this NSAID-induced apoptosis in primary cultures of gastric mucosal cells. Various NSAIDs showed membrane permeabilization activity that correlated with their apoptosis-inducing activity. Various NSAIDs, particularly celecoxib, also increased intracellular Ca2+ levels. This increase was accompanied by K+ efflux from cells and was virtually absent when extracellular Ca2+ had been depleted. These data indicate that the increase in intracellular Ca2+ levels that is observed in the presence of NSAIDs is due to the stimulation of Ca2+ influx across the cytoplasmic membrane, which results from their membrane permeabilization activity. An intracellular Ca2+ chelator partially inhibited celecoxib-induced release of cytochrome c from mitochondria, reduced the magnitude of the celecoxib-induced decrease in mitochondrial membrane potential and inhibited celecoxib-induced apoptotic cell death. It is therefore likely that an increase in intracellular Ca2+ levels is involved in celecoxib-induced mitochondrial dysfunction and the resulting apoptosis. ATI inhibitor of calpain, a Ca2+-dependent cysteine protease, partially suppressed mitochondrial dysfunction and apoptosis in the presence of celecoxib. Celecoxib-dependent CHOP-induction was partially inhibited by the intracellular Ca2+ chelator but not by the calpain inhibitor. These results suggest that Ca2+-stimulated calpain activity and CHOP expression play important roles in celecoxib-induced apoptosis in gastric mucosal cells. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

DOI： 10.1074/jbc.M502956200

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Language：English   Publisher：ROYAL SOC CHEMISTRY  

The transition-metal-catalyzed rearrangement of 5-alkynals to gamma-alkynylketones and 1-cyclopentenylketones was developed using [Rh(P(OPh)(3))(2)]BF4 or Cu(OTf)(2) as a catalyst.

DOI： 10.1039/b508278a

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Language：English   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

The cytotoxicity of non-steroidal anti-inflammatory drugs (NSAIDs) is involved in the formation of NSAID-induced gastric lesions. The mechanism(s) behind these cytotoxic effects, however, is not well understood. We found here that several NSAIDs tested caused hemolysis when employed at concentrations similar to those that result in cytotoxicity. Moreover, these same NSAIDs were found to directly permeabilize the membranes of calcein-loaded liposomes. Given the similarity in NSAID concentrations for cytotoxic and membrane permeabilization effects, the cytotoxic action of these NSAIDs may be mediated through the permeabilization of biological membranes. Increase in the intracellular Ca2+ level can lead to cell death. We here found that all of NSAIDs tested increased the intracellular Ca2+ level at concentrations similar to those that result in cytotoxicity. Based on these results, we consider a possibility that membrane permeabilization by NSAIDs induces cell death through increase in the intracellular Ca2+ level. (C) 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2004.08.205

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Language：English   Publisher：CHEMICAL SOC JAPAN  

The synthesis of the indolizidine alkaloid (+/-)-monomorine I has successfully been achieved by a new route starting with a one-pot four-component connecting reaction based on a palladium-catalyzed carbonylative 1,4-addition of an organozinc halide to a alpha,beta-enone in an atmosphere of carbon monoxide.

DOI： 10.1246/bcsj.77.1031

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DOI： 10.1023/B:JOEC.0000045597.51021.f8

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The stereo-structure of piperidine lactone (3), a synthetic intermediate of the antimalarial agent febrifugine ((+)-1) with a piperidine ring in the trans relative configuration, was re-revised to the cis-form. We determined that isomerization to the trans-form from the cis-form occurred in the stage (6 from 5) of deprotection in Baker's synthesis. (C) 2003 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4020(03)00139-X

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Transglucosylation activities of spinach α-glucosidase I and IV, which have different substrate specificity for hydrolyzing activity, were investigated. In a maltose mixture, α-glucosidase I, which has high activity toward not only maltooligosaccharides but also soluble starch and can hydrolyze isomaltose, produced maltotriose, isomaltose, and panose, and α-glucosidase IV, which has high activity toward maltooligosaccharides but faint activity toward soluble starch and isomaltose, produced maltotriose, kojibiose, and 2,4-di-α-D-glucosyl-glucose. Transglucosylation to sucrose by α-glucosidase I and IV resulted in the production of theanderose and erlose, respectively, showing that spinach α-glucosidase I and IV are useful to synthesize the α-1,6-glucosylated and α-1,2- and 1,4-glucosylated products, respectively. © 1999 by Japan Society for Bioscience, Biotechnology, and Agrochemistry.

DOI： 10.1271/bbb.67.1160

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DOI： 10.1248/cpb.51.175

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Language：English   Publisher：AMER CHEMICAL SOC  

A series of novel monoacylated vitamin C derivatives were chemically synthesized with a stable ascorbate derivative, 2-O-alpha-D-glucopyranosyl-L-ascorbic acid (AA-2G), and acid anhydrides in pyridine. Their solubility in organic phase, thermal stability, radical scavenging activity, and in vitro skin permeability was evaluated. These monoacylated derivatives were identified as 6-O-acyl-2-O-alpha-D-glucopyranosyl-L-ascorbic acids (6-Acyl-AA-2G) by UV spectra, elemental analyses, and nuclear magnetic resonance spectroscopy. The reactions afforded 6-Acyl-AA-2G in high yields (30-60%). 6-Acyl-AA-2G exhibited satisfactory stability in neutral solution comparable to that of atypical stable derivative, AA-2G, and also showed the radical scavenging activity. The lipid solubility of 6-Acyl-AA-2G was increased with increasing length of their acyl group. Increased skin permeability was superior to those of AA-2G and ascorbic acid (AsA). 6-Acyl-AA-2G that is susceptible to enzymatic hydrolysis by tissue esterase and/or alpha-glucosidase produces AA-2G and AsA, which is in the skin tissues. Thus, these findings indicate that the novel vitamin C derivatives presented here, 6-Acyl-AA-2G, may be effective antioxidants in skin care and medicinal use.

DOI： 10.1021/jm010379f

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DOI： 10.1021/jm010379f

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DOI： 10.1002/jhet.5570390312

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Language：English   Publisher：HeteroCorporation  

New functionalized maleimides (3-methylthio-2,5-dioxo-1H-pyrroles) were obtained by the reaction of ketene dithioacetals with nitromethane or the reaction of nitro ketene dithioacetal with active methylene compounds in the presence of the appropriate base in dimethyl sulfoxide followed by treatment with methanol. These maleimides reacted with various nucleophilic reagents such as electron-rich aromatic and heteroaromatic compounds like dialkylanilines, aminophenols, indoles, indolizines, and cyalazines to give the corresponding 3-aryl- or heteroaryl-1H-pyrole-2,5-diones. Styryl and merocyanine dyes, and polycyclic pyridazine-diones as chemiluminophors and succinimides were also obtained from these maleimides with good results.

DOI： 10.1002/jhet.5570390312

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DOI： 10.1248/bpb.25.761

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DOI： 10.1248/cpb.50.1011

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DOI： 10.1016/S0003-9861(02)00485-X

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DOI： 10.1002/jhet.5570380218

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DOI： 10.1248/bpb.24.1404

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DOI： 10.1248/bpb.24.529

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DOI： 10.3987/COM-01-9168

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DOI： 10.1002/jhet.5570380313

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DOI： 10.1248/bpb.24.378

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DOI： 10.1002/jhet.5570370446

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Naphtho[1, 2-b][1]benzothiophene-6-carboxylic acids, 6H-benzo[b]naphtho[2, 3-d]thiopyran-6-ones and 6H-benzo[b]naphtho[2, 3-d]pyran-6-ones were synthesized in one step by the photocyclization reaction of 3-aryl-2-([1]benzothien-3-yl)propenoic acids. The photocyclization reaction did not occur when the 3-aryl group contained the electron-withdrawing nitro group. The assignment of the 1H and 13C nmr spectra of 6H-benzo[b]naphtho[2, 3-d]thiopyran-6-one and 6H-benzo[b]naphtho[2, 3-d]pyran-6-one by two-dimensional nmr methods is described. The difference between the chemical shift values of H12 for these two compounds is attributed to different molecular geometries.

DOI： 10.1002/jhet.5570370446

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Language：English   Publisher：Japan Institute of Heterocyclic Chemistry  

Substituted anilines reacted with methyl 1-methyl-4-methylthio-2,5- dioxo-3-pyrroline-3-carboxylate (1) in refluxing methanol to give the corresponding methyl 1-methyl-2,5-dioxo-4-phenylamino-3-pyrroline-3- carboxylates (3a-e) which were converted in good yields to 2- methylpyrrolo[3,4-b]quinoline derivatives (4a-e) by heating in diphenyl ether. Reaction of 4a-e with hydrazine hydrate gave 10-hydroxypyridazino[4,5- b]quinoline-1,4(2H,3H)-diones (5a-e) in good yields. The desired 10- aminopyridazino[4,5-b]quinoline-1,4(2H, 3H)-diones (8a-e) were obtained by the chlorination of 4a-e with phosphorus oxychloride followed by ammonolysis with 28% ammonium hydroxide in good yields. Compounds (5) and (8) were found to be efficiently chemiluminescent in a similarly to luminol in the presence of H2O2 and horseradish peroxidase in a solution of a phosphate buffer pH 8.0.

DOI： 10.3987/COM-98-S(H)20

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The reactions of N-(5,6-dihydro[1]benzothiepino[5,4-d]pyrimidin-4- yl)amidines or its amide oxime derivatives with hydroxylamine hydrochloride under basic condition gave abnormal cyclization products via a ring cleavage of pyrimidine component accompanied with a ring closure of [1,2,4]oxadiazole.

DOI： 10.1002/jhet.5570360335

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Language：English   Publisher：HeteroCorporation  

The reactions of N-(5,6-dihydro[1]benzothiepino[5,4-d]pyrimidin-4- yl)amidines or its amide oxime derivatives with hydroxylamine hydrochloride under basic condition gave abnormal cyclization products via a ring cleavage of pyrimidine component accompanied with a ring closure of [1,2,4]oxadiazole.

DOI： 10.1002/jhet.5570360335

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DOI： 10.1002/jhet.5570360335

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Language：English   Publisher：HeteroCorporation  

Some novel 5-hydroxyalkylamino-1,2-dihydrothieno[2,3- h][1,6]naphthyridines were prepared by the reaction of 5-chloro-l,2- dihydrothieno[2,3-h][1,6]naphthyridine derivatives with some aminoalcohols in the presence of base. These derivatives were cyclized to the corresponding imidazo or pyrimido derivatives. The bronchodilatory activity of these compounds was evaluated on the basis of their relaxation activity to tracheal contraction induced by carbamylcholine chloride as a primary in vitro assays. Effect of some naphthyridines on carbamylcholine chloride-induced contractions of trachea in the presence or absence of milrinone or 4-(3- butoxy-4-methoxyphenyl)imidazolidin-2-one, which is inhibitor of phosphodiesterase III or IV, were also evaluated.

DOI： 10.1002/jhet.5570360221

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Language：English   Publisher：HeteroCorporation  

Some novel 5-hydroxyalkylamino-1,2-dihydrothieno[2,3- h][1,6]naphthyridines were prepared by the reaction of 5-chloro-l,2- dihydrothieno[2,3-h][1,6]naphthyridine derivatives with some aminoalcohols in the presence of base. These derivatives were cyclized to the corresponding imidazo or pyrimido derivatives. The bronchodilatory activity of these compounds was evaluated on the basis of their relaxation activity to tracheal contraction induced by carbamylcholine chloride as a primary in vitro assays. Effect of some naphthyridines on carbamylcholine chloride-induced contractions of trachea in the presence or absence of milrinone or 4-(3- butoxy-4-methoxyphenyl)imidazolidin-2-one, which is inhibitor of phosphodiesterase III or IV, were also evaluated.

DOI： 10.1002/jhet.5570360221

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DOI： 10.1002/jhet.5570360221

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DOI： 10.1039/a809077g

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Language：English   Publisher：Royal Society of Chemistry  

The synthesis of abnormal cyclization products, 2-(3-alkyl(or aryl)[1,2,4]oxadiazol-5-yl)-3,4-dihydro-1-naphthylaminoformaldehyde oximes and their homologues, by the reaction of N-(benzo[h]quinazolin-4-yl)amidine or its amide oxime derivatives with excess NH2OH·HCl are described.

DOI： 10.1039/a809077g

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Language：English   Publisher：Royal Society of Chemistry  

The synthesis of abnormal cyclization products, 2-(3-alkyl(or aryl)[1,2,4]oxadiazol-5-yl)-3,4-dihydro-1-naphthylaminoformaldehyde oximes and their homologues, by the reaction of N-(benzo[h]quinazolin-4-yl)amidine or its amide oxime derivatives with excess NH2OH·HCl are described.

DOI： 10.1039/a809077g

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DOI： 10.1039/a809077g

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DOI： 10.3987/COM-98-S(H)20

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Language：English   Publisher：The Pharmaceutical Society of Japan  

The effect of three positional isomers, o-, m- and p-acetylaminophenyl sulfate (AOAPS, AMAPS and APAPS (acetaminophen sulfate), respectively), on the pharmacokinetics of acetaminophen (APAP) was investigated in rats. All of the intravenously administered positional isomers were rapidly eliminated from plasma, and approximately 80% of the dose was excreted in an unchanged form in the urine within 4 h, while biliary excretions represented a small percent of the doses. Following the intravenous bolus injection of APAP, plasma elimination of APAP was accelerated and the distribution volume of APAP was increased under a steady state concentration (about 10 μg APAP eq/ml) of AOAPS or APAPS, but not AMAPS, as compared with saline infusion. Total body clearances of APAP were increased from 18.3 ml/min/kg for the control to 23.9 and 26.9 ml/min/kg for AOAPS and APAPS coadministration, respectively. AOAPS and APAPS competitively displaced the serum protein binding of APAP, while AMAPS had little effect. The distribution volume of unbound APAP was anomalously increased by APAPS, while it was not affected by AOAPS or AMAPS. Tissue-to-plasma concentration ratios of APAP were significantly increased by APAPS in the liver, kidney and brain, while they were only slightly increased by AOAPS. It was suggested that APAPS has nt only the displacing activity of serum protein binding but also other specific effectiveness on the distribution of APAP.

DOI： 10.1248/bpb.20.522

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Other Link： https://jlc.jst.go.jp/DN/JALC/00083788598?from=CiNii

Language：English   Publisher：The Pharmaceutical Society of Japan  

The effect of three positional isomers, o-, m- and p-acetylaminophenyl sulfate (AOAPS, AMAPS and APAPS (acetaminophen sulfate), respectively), on the pharmacokinetics of acetaminophen (APAP) was investigated in rats. All of the intravenously administered positional isomers were rapidly eliminated from plasma, and approximately 80% of the dose was excreted in an unchanged form in the urine within 4 h, while biliary excretions represented a small percent of the doses. Following the intravenous bolus injection of APAP, plasma elimination of APAP was accelerated and the distribution volume of APAP was increased under a steady state concentration (about 10 μg APAP eq/ml) of AOAPS or APAPS, but not AMAPS, as compared with saline infusion. Total body clearances of APAP were increased from 18.3 ml/min/kg for the control to 23.9 and 26.9 ml/min/kg for AOAPS and APAPS coadministration, respectively. AOAPS and APAPS competitively displaced the serum protein binding of APAP, while AMAPS had little effect. The distribution volume of unbound APAP was anomalously increased by APAPS, while it was not affected by AOAPS or AMAPS. Tissue-to-plasma concentration ratios of APAP were significantly increased by APAPS in the liver, kidney and brain, while they were only slightly increased by AOAPS. It was suggested that APAPS has nt only the displacing activity of serum protein binding but also other specific effectiveness on the distribution of APAP.

DOI： 10.1248/bpb.20.522

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Other Link： https://jlc.jst.go.jp/DN/JALC/00083788598?from=CiNii

Language：English  

The effect of conjugated-metabolite, acetaminophen sulfate (APAPS), on the pharmacokinetics of its parent drug, acetaimnophen (APAP), was examined in rats. Following the i.v. bolus administration of APAP with APAPS, the plasma elimination of APAP was delayed and the distribution volume of APAP was increased at the APAPS coadministration with 60 mg APAP equivalent per kg (eq/kg). The percentages of dose excreted in the urine and bile in 4 h as APAP and its conjugated metabolites, APAPS and acetaminophen glucuronide, were significantly decreased. On the other hand, following the i.v. bolus administration of APAP under the steady-state concentration of APAPS, the distribution volume and total body clearance of APAP were significantly increased. Competitive displacement in serum protein binding of APAP by APAPS was ascertained in vitro and in vivo. A part of the conflict between the bolus and infusion experiment may be explained by the changes in the distribution volume of APAP contributed to the APAPS concentration-dependent serum protein binding of APAP. It was speculated that the pharmacokinetics of APAP was partly interacted with APAPS by the displacement of serum protein binding.

DOI： 10.1016/S0378-5173(96)04803-X

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The effect of conjugated-metabolite, acetaminophen sulfate (APAPS), on the pharmacokinetics of its parent drug, acetaimnophen (APAP), was examined in rats. Following the i.v. bolus administration of APAP with APAPS, the plasma elimination of APAP was delayed and the distribution volume of APAP was increased at the APAPS coadministration with 60 mg APAP equivalent per kg (eq/kg). The percentages of dose excreted in the urine and bile in 4 h as APAP and its conjugated metabolites, APAPS and acetaminophen glucuronide, were significantly decreased. On the other hand, following the i.v. bolus administration of APAP under the steady-state concentration of APAPS, the distribution volume and total body clearance of APAP were significantly increased. Competitive displacement in serum protein binding of APAP by APAPS was ascertained in vitro and in vivo. A part of the conflict between the bolus and infusion experiment may be explained by the changes in the distribution volume of APAP contributed to the APAPS concentration-dependent serum protein binding of APAP. It was speculated that the pharmacokinetics of APAP was partly interacted with APAPS by the displacement of serum protein binding.

DOI： 10.1016/S0378-5173(96)04803-X

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Language：English   Publisher：Japan Institute of Heterocyclic Chemistry  

Reaction of l-methyl-3-methylthiomaleimides (1a-c) with N,N-dialkylanilines (2) under refluxing in acetic acid condition gave the corresponding 3-(4-diakylamino)phenyl-1-methylmaleimides (3a-g). Treatment of these 1-methyl-3-phenylmaleimides (3a, c) with Lawesson's reagent under refluxing in toluene afforded new blue dyes, 4-(4-dialkylamino)phenyl-3-cyano-1-methyl-5-oxopyrrole-2-thiones (5a, b) which are brilliant blue dyes appearing at 606 and 615 nm (log ε: 4.59 and 4.50) in UV spectra. Reaction of 4-methoxycarbonyl-1-methyl-3-methylthiomaleimide (1b) with 3-dialkylamino-phenol under the same reaction conditions gave cyclizcd products, 2H, 4H-[1]-benzopyrano[3,4-c]pyrrole-1,3,4-triones (6a-c) in good yields.

DOI： 10.3987/COM-97-S12

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Language：English   Publisher：Japan Institute of Heterocyclic Chemistry  

Reaction of l-methyl-3-methylthiomaleimides (1a-c) with N,N-dialkylanilines (2) under refluxing in acetic acid condition gave the corresponding 3-(4-diakylamino)phenyl-1-methylmaleimides (3a-g). Treatment of these 1-methyl-3-phenylmaleimides (3a, c) with Lawesson's reagent under refluxing in toluene afforded new blue dyes, 4-(4-dialkylamino)phenyl-3-cyano-1-methyl-5-oxopyrrole-2-thiones (5a, b) which are brilliant blue dyes appearing at 606 and 615 nm (log ε: 4.59 and 4.50) in UV spectra. Reaction of 4-methoxycarbonyl-1-methyl-3-methylthiomaleimide (1b) with 3-dialkylamino-phenol under the same reaction conditions gave cyclizcd products, 2H, 4H-[1]-benzopyrano[3,4-c]pyrrole-1,3,4-triones (6a-c) in good yields.

DOI： 10.3987/COM-97-S12

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Language：English   Publisher：Elsevier B.V.  

N-Acetyl-S-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]-L-cysteine (I), a new imidazole compound with a sulfur-containing side chain, was isolated from normal human urine by ion-exchange column chromatography, and characterized by physicochemical analyses involving 1H-NMR spectrometry, mass spectrometry and high-voltage paper electrophoresis as well as chemical synthesis. Approximately five milligrams of crystals of the compound were obtained from 450 litres of the urine. Compound I was synthesized by the addition of N-acetyl-L-cysteine to urocanic acid. The compound was also formed by incubation of S-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]-L-cysteine (II) with acetyl-CoA in the use of rat kidney or liver homogenate as an enzyme source in a Tris buffer at pH 7.4. Rat brain and spleen homogenates were the less or no effective preparations as the enzyme source. On the other hand, little N-acetylation of a diastereomer of compound II occurred in enzymatic reactions with rat tissue homogenates. Compound I was degraded to compound II by rat kidney or liver homogenate. These results suggest that compound I is a new N-acetylated metabolite of compound II, a compound previously found in human urine, and that the acetylating enzyme recognizes stereoisomerism of asymmetric carbon atoms on the molecule of compound II. These findings support an alternative pathway of L-histidine catabolism initiated by the adduction of glutathione and/or cysteine to urocanic acid, the first catabolite of histidine.

DOI： 10.1016/0304-4165(96)00055-4

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Language：English   Publisher：Elsevier B.V.  

N-Acetyl-S-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]-L-cysteine (I), a new imidazole compound with a sulfur-containing side chain, was isolated from normal human urine by ion-exchange column chromatography, and characterized by physicochemical analyses involving 1H-NMR spectrometry, mass spectrometry and high-voltage paper electrophoresis as well as chemical synthesis. Approximately five milligrams of crystals of the compound were obtained from 450 litres of the urine. Compound I was synthesized by the addition of N-acetyl-L-cysteine to urocanic acid. The compound was also formed by incubation of S-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]-L-cysteine (II) with acetyl-CoA in the use of rat kidney or liver homogenate as an enzyme source in a Tris buffer at pH 7.4. Rat brain and spleen homogenates were the less or no effective preparations as the enzyme source. On the other hand, little N-acetylation of a diastereomer of compound II occurred in enzymatic reactions with rat tissue homogenates. Compound I was degraded to compound II by rat kidney or liver homogenate. These results suggest that compound I is a new N-acetylated metabolite of compound II, a compound previously found in human urine, and that the acetylating enzyme recognizes stereoisomerism of asymmetric carbon atoms on the molecule of compound II. These findings support an alternative pathway of L-histidine catabolism initiated by the adduction of glutathione and/or cysteine to urocanic acid, the first catabolite of histidine.

DOI： 10.1016/0304-4165(96)00055-4

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Language：English   Publisher：HeteroCorporation  

Synthesis of 11-substituted 1,2,4,5-tetrahydrobenzo[h]imidazo[1,2-c]quinazolines corresponding to 12-substituted 11,13,15-triazasteroid is described. Evaluation on inhibitory activity against collagen-induced platelet aggregation of these compounds and their precursors was also investigated.

DOI： 10.1002/jhet.5570330619

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Language：English   Publisher：HeteroCorporation  

The novel polycyclic heterocyclic ring system, naphtho[2,1-b:4,3-g]bisbenzo[b]thiophene was synthesized from 5-[2-(2-bromo-3-thienyl)ethenyl]naphtho[2,1-b][1]benzothiophene. The assignment of its 1H and 13C nmr spectra was also accomplished by utilizing two-dimensional nmr methods.

DOI： 10.1002/jhet.5570330351

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Language：English   Publisher：HeteroCorporation  

Synthesis of 11-substituted 1,2,4,5-tetrahydrobenzo[h]imidazo[1,2-c]quinazolines corresponding to 12-substituted 11,13,15-triazasteroid is described. Evaluation on inhibitory activity against collagen-induced platelet aggregation of these compounds and their precursors was also investigated.

DOI： 10.1002/jhet.5570330619

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Language：English   Publisher：HeteroCorporation  

The novel polycyclic heterocyclic ring system, naphtho[2,1-b:4,3-g]bisbenzo[b]thiophene was synthesized from 5-[2-(2-bromo-3-thienyl)ethenyl]naphtho[2,1-b][1]benzothiophene. The assignment of its 1H and 13C nmr spectra was also accomplished by utilizing two-dimensional nmr methods.

DOI： 10.1002/jhet.5570330351

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An efficient methodology for the synthesis of novel ring system, thieno[2,3-h][1,6]naphthyridine, via a Smiles type rearrangement reaction and cyclization is described, its structure is confirmed by an X-ray structure analysis.

DOI： 10.1039/C39940001767

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An efficient methodology for the synthesis of novel ring system, thieno[2,3-h][1,6]naphthyridine, via a Smiles type rearrangement reaction and cyclization is described, its structure is confirmed by an X-ray structure analysis.

DOI： 10.1039/C39940001767

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Synthesis of benzo[3,4]cyclohepta[1,2‐e]pyrimido[1,2‐c]pyrimidines, corresponding to the B,D‐dihomo‐11,13,15‐triazasteroidal skeleton as a novel ring system is described. Their effects on reserpine‐induced hypothermia in mice and inhibitory activity against collagen‐induced platelet aggregation were also investigated. Copyright © 1993 Journal of Heterocyclic Chemistry

DOI： 10.1002/jhet.5570300425

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Language：English  

Synthesis of benzo[3,4]cyclohepta[1,2‐e]pyrimido[1,2‐c]pyrimidines, corresponding to the B,D‐dihomo‐11,13,15‐triazasteroidal skeleton as a novel ring system is described. Their effects on reserpine‐induced hypothermia in mice and inhibitory activity against collagen‐induced platelet aggregation were also investigated. Copyright © 1993 Journal of Heterocyclic Chemistry

DOI： 10.1002/jhet.5570300425

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Syntheses of 11,13,15,17‐tetraazasteroids, their B‐homologues, and 17‐oxide derivatives are described. Antidepressive evaluation of these compounds and their precursors were screened by inhibitory action of reserpine‐induced hypothermia. Copyright © 1991 Journal of Heterocyclic Chemistry

DOI： 10.1002/jhet.5570280209

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Syntheses of 11,13,15,17‐tetraazasteroids, their B‐homologues, and 17‐oxide derivatives are described. Antidepressive evaluation of these compounds and their precursors were screened by inhibitory action of reserpine‐induced hypothermia. Copyright © 1991 Journal of Heterocyclic Chemistry

DOI： 10.1002/jhet.5570280209

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Synthesis of 4‐(2‐hydroxyethylamino)‐6,7‐dihydro‐5H‐benzo[6,7]cyclohepta[1,2‐d]pyrimidine derivatives V and their cyclized products, B‐homo‐11,13,15‐triazasteroidal compounds VI and VII, are described. These products were screened to evaluate the antidepressive activity. Copyright © 1990 Journal of Heterocyclic Chemistry

DOI： 10.1002/jhet.5570270352

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Synthesis of 4‐(2‐hydroxyethylamino)‐6,7‐dihydro‐5H‐benzo[6,7]cyclohepta[1,2‐d]pyrimidine derivatives V and their cyclized products, B‐homo‐11,13,15‐triazasteroidal compounds VI and VII, are described. These products were screened to evaluate the antidepressive activity. Copyright © 1990 Journal of Heterocyclic Chemistry

DOI： 10.1002/jhet.5570270352

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Syntheses of novel 15‐thia‐11,13‐diazasteroidal skeleton IV and its D‐homo analogues are described. Meso‐ionic derivatives of IV were also synthesized. Antidepressive activities of these compounds and their precursors were screened. D‐Dihomothiadiazasteroid IX and 3,4,5,6‐tetrahydrobenzo[h]quinazoline‐4‐thione (V) exhibited antireserpine action. Copyright © 1987 Journal of Heterocyclic Chemistry

DOI： 10.1002/jhet.5570240209

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Language：English  

Syntheses of novel 15‐thia‐11,13‐diazasteroidal skeleton IV and its D‐homo analogues are described. Meso‐ionic derivatives of IV were also synthesized. Antidepressive activities of these compounds and their precursors were screened. D‐Dihomothiadiazasteroid IX and 3,4,5,6‐tetrahydrobenzo[h]quinazoline‐4‐thione (V) exhibited antireserpine action. Copyright © 1987 Journal of Heterocyclic Chemistry

DOI： 10.1002/jhet.5570240209

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A synthesis of 1,2,5,6‐tetrahydro‐4H‐benzo[3,4]cyclohepta[1,2‐e]imidazo[1,2‐c]pyrimidine (XII) having a novel ring system is described. Antidepressive activity of XII and its precursors VII‐X was screened by inhibitory action of reserpine‐induced hypothermia. Copyright © 1986 Journal of Heterocyclic Chemistry

DOI： 10.1002/jhet.5570230616

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A novel synthesis of 2‐benzofurancarbaldehydes by the Vilsmeier reaction of phenoxyacetaldehyde diethyl acetals is described. Copyright © 1986 Journal of Heterocyclic Chemistry

DOI： 10.1002/jhet.5570230622

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A novel synthesis of 2‐benzofurancarboxylic acid derivatives by the Vilsmeier reaction of phenoxyacetonitriles is described. Copyright © 1986 Journal of Heterocyclic Chemistry

DOI： 10.1002/jhet.5570230516

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Language：English  

A novel synthesis of 2‐benzofurancarbaldehydes by the Vilsmeier reaction of phenoxyacetaldehyde diethyl acetals is described. Copyright © 1986 Journal of Heterocyclic Chemistry

DOI： 10.1002/jhet.5570230622

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Language：English  

A synthesis of 1,2,5,6‐tetrahydro‐4H‐benzo[3,4]cyclohepta[1,2‐e]imidazo[1,2‐c]pyrimidine (XII) having a novel ring system is described. Antidepressive activity of XII and its precursors VII‐X was screened by inhibitory action of reserpine‐induced hypothermia. Copyright © 1986 Journal of Heterocyclic Chemistry

DOI： 10.1002/jhet.5570230616

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Language：English  

A novel synthesis of 2‐benzofurancarboxylic acid derivatives by the Vilsmeier reaction of phenoxyacetonitriles is described. Copyright © 1986 Journal of Heterocyclic Chemistry

DOI： 10.1002/jhet.5570230516

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