研究者詳細 - 佐々木　健二

MISC - 佐々木　健二

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Polycyclic N-Heterocyclic Compounds. Part 85: Synthesis and Evaluation of Antiplatelet Aggregation Activity of 2,4-Disubstituted 5,6-Dihydro[1]benzazepino[5,4-d]pyrimidine and Related Compounds

Kensuke Okuda, Ying-Xue Zhang, Takashi Hirota, Kenji Sasaki

JOURNAL OF HETEROCYCLIC CHEMISTRY 52 ( 3 ) 888 - 895 2015年5月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

We have synthesized a large number of tricyclic 2-substituted 4-alkylamino-5,6-dihydro[1]benzazepino[5,4-d]pyrimidines as part of our research to develop new effective antiplatelet 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 antiplatelet candidates with potencies superior to aspirin.

DOI： 10.1002/jhet.2040

Polycyclic N-Heterocyclic Compounds. Part 86: Synthesis and Evaluation of Antiplatelet Aggregation Activity of 2,4-Disubstituted 9-Chloro-5,6-dihydropyrimido[5,4-d]benzazepine and Related Compounds

Kensuke Okuda, Shigeki Takarada, Takashi Hirota, Kenji Sasaki

JOURNAL OF HETEROCYCLIC CHEMISTRY 52 ( 3 ) 780 - 792 2015年5月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

Libraries of tricyclic 2-substituted 4-alkylamino-9-chloro-5,6-dihydropyrimido[5,4-d]benzazepines and tetracyclic 12-substituted 8-chloro-1,2,5,6-tetrahydro-4H-imidazo[1,2:1,6]pyrimido[5,4-d]benzazepines 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.2190

SYNTHESIS, BIOLOGICAL ACTIVITIES, AND TAUTOMERISM OF 4-QUINOLONES AND RELATED COMPOUNDS

Yoshihisa Kurasawa, Kenji Sasaki

HETEROCYCLES 91 ( 1 ) 1 - 39 2015年1月

記述言語：英語掲載種別：書評論文，書評，文献紹介等出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

This review describes the synthesis, biological activities, and tautomerism of various 4-quinolones together with related compounds including 4-oxopyridazino[3,4-b]quinoxalines (bioisostere of 4-quinolones).

DOI： 10.3987/REV-14-806

Quinolone Analogs 16: A Facile D-H Exchange for 3-H Proton of 2-Substituted 4-Quinolones in Acidic Media

Yoshihisa Kurasawa, Kiminari Yoshida, Naoki Yamazaki, Kenji Sasaki, Yoshito Zamami, Zhao Min, Atsumi Togi, Hideyuki Ito, Eisuke Kaji, Haruhiko Fukaya

JOURNAL OF HETEROCYCLIC CHEMISTRY 51 ( 6 ) 1821 - 1829 2014年11月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

The 4-quinolones having the urea or carbamate moiety at the 2-position showed the facile deuterium-hydrogen (D-H) exchange of the 3-H proton in deuteriotrifluoroacetic acid-deuteriodimethyl sulfoxide (3:1) at 60 degrees C, whereas the 4-quinolones possessing the carboxylate or carbohydrazide group at the 2-position and 2-substituted 4-methoxyquinolines represented no D-H exchange of the 3-H proton under the same condition. The aforementioned D-H exchange was found to require both the tautomerization of the 4-quinolone into 4-hydroxyquinoline in strongly acidic media and the nitrogen functional group at the 2-position.

DOI： 10.1002/jhet.1933

Quinolone Analogs 13: Synthesis of Novel 1,1 '-(2-Methylenepropane-1,3-diyl)di(4-quinolone-3-carboxylate) and Related Compounds

Yoshihisa Kurasawa, Kiminari Yoshida, Naoki Yamazaki, Eisuke Kaji, Kenji Sasaki, Yoshito Zamami, Takatoshi Fujii, Min Zhao, Hideyuki Ito, Haruhiko Fukaya

JOURNAL OF HETEROCYCLIC CHEMISTRY 51 ( 6 ) 1720 - 1726 2014年11月

記述言語：英語出版者・発行元：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

Polycyclic N-Heterocyclic Compounds. Part 79: Synthesis of 2,4-Disubstituted 6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidines as Potential Antiplatelet Aggregators

Kensuke Okuda, Takashi Hirota, Kenji Sasaki

JOURNAL OF HETEROCYCLIC CHEMISTRY 51 ( 6 ) 1607 - 1614 2014年11月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

Libraries of tricyclic 2-substituted 4-alkylamino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]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.1714

Quinolone Analogues 15: Synthesis and Antimalarial Activity of 4-Phenyl-1-(1-triazolylmethyl-4-quinolon-3-ylcarbonyl)semicarbazide and Related Compounds

Yoshihisa Kurasawa, Kiminari Yoshida, Naoki Yamazaki, Kenji Sasaki, Yoshito Zamami, Zhao Min, Atsumi Togi, Hideyuki Ito, Eisuke Kaji, Haruhiko Fukaya

JOURNAL OF HETEROCYCLIC CHEMISTRY 51 ( S1 ) E249 - E254 2014年8月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

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

Polycyclic N-Heterocyclic Compounds. Part 80: Synthesis and Evaluation of Effects on In Vitro Pentosidine Formation of 5,6-Dihydro[1]benzothieno [3 ',2 ':2,3]thiepino[4,5-d]pyrimidine and Related Compounds

Kensuke Okuda, Yutaka Itsuji, Takashi Hirota, Kenji Sasaki

JOURNAL OF HETEROCYCLIC CHEMISTRY 51 ( 4 ) 891 - 898 2014年7月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

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

Polycyclic N-Heterocyclic Compounds. Part 82: Synthesis and Evaluation of Anti-Platelet Aggregation Activity of 2,4-Disubstituted 5,6-Dihydro[1]benzothiepino[5,4-d]pyrimidine and Related Compounds

Kensuke Okuda, Takashi Hirota, Kenji Sasaki

JOURNAL OF HETEROCYCLIC CHEMISTRY 51 ( 4 ) 911 - 920 2014年7月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

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

Polycyclic N-Heterocyclic Compounds. Part 75: Synthesis of 2,4-Disubstituted 5,6-dihydro[1]benzoxepino[5,4-d]pyrimidines and 12-Substituted 1,2,4,5-Tetrahydro[1]benzoxepino[4,5-e]imidazo[1,2-c]pyrimidines as Potential Antiplatelet Aggregators

Kensuke Okuda, Yuko Yamamoto, Takashi Hirota, Kenji Sasaki

JOURNAL OF HETEROCYCLIC CHEMISTRY 51 ( 4 ) 972 - 981 2014年7月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

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

Polycyclic N-heterocyclic compounds. Part 83. Synthesis of 2,4-disubstituted 5,6-dihydro[1]benzofuro[3',2':2,3]oxepino[4,5-d]pyrimidines and 2,4,5-trisubstituted 5,6-dihydro[1]benzofuro[2',3':5,6]pyrano[4,3-d]pyrimidines from 4-chloro-5,6-dihydro[1]ben・・・

Kensuke Okuda, Jun-ichi Takano, Takashi Hirota, Kenji Sasaki

Journal of Heterocyclic Chemistry 51 ( 3 ) 788 - 793 2014年5月

Polycyclic N-Heterocyclic Compounds 76: Synthesis and Antiplatelet Evaluation of 2,4-Disubstituted 5,6-Dihydro[1]benzofuro[3',2':2,3]oxepino[4,5-d]pyrimidines

Kensuke Okuda, Jun-ichi Takano, Takashi Hirota, Kenji Sasaki, Yuta Nishina, Hiroyuki Ishida

JOURNAL OF HETEROCYCLIC CHEMISTRY 51 ( 3 ) 661 - 668 2014年5月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

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

Polycyclic N-Heterocyclic Compounds. Part 78: Synthesis of N-[2-([1,2,4] Oxadiazol-5-yl) cyclohepten-1-yl]formamide Oximes and Their Evaluation as Inhibitors of Platelet Aggregation

Kensuke Okuda, Ying-Xue Zhang, Takashi Hirota, Kenji Sasaki

JOURNAL OF HETEROCYCLIC CHEMISTRY 51 ( 2 ) 518 - 522 2014年3月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

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

POLYCYCLIC N-HETEROCYCLIC COMPOUNDS, PART 77: SYNTHESIS OF [1]BENZOTHIENO[3 ',2 ':2,3]OXEPINO[4,5-d]PYRIMIDINES AND EVALUATION OF THEIR ANTIPLATELET AGGREGATION ACTIVITY

Kensuke Okuda, Takashi Nikaido, Takashi Hirota, Kenji Sasaki

SYNTHETIC COMMUNICATIONS 43 ( 12 ) 1619 - 1625 2013年6月

記述言語：英語出版者・発行元：TAYLOR & FRANCIS INC

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

Polycyclic N-Heterocyclic Compounds 73: Synthesis and Evaluation of 5-Substituted 1,2-Dihydrofuro[2,3-c]isoquinolines as Inducers of Lipoprotein Lipase mRNA Expression

Kensuke Okuda, Masahiko Yoshida, Takashi Hirota, Kenji Sasaki

JOURNAL OF HETEROCYCLIC CHEMISTRY 50 ( 51 ) E9 - E11 2013年2月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

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

Novel quercetin glycosides as potent anti-mrsa and anti-vre agents

Abugafar M.L. Hossion, Kenji Sasaki

Recent Patents on Anti-Infective Drug Discovery 8 ( 3 ) 198 - 205 2013年

記述言語：英語出版者・発行元：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

Quinolone Analogues 12: Synthesis and Tautomers of 2-Substituted 4-Quinolones and Related Compounds

Yoshihisa Kurasawa, Kiminari Yoshida, Naoki Yamazaki, Kotoji Iwamoto, Yoshihiko Hamamoto, Eisuke Kaji, Kenji Sasaki, Yoshito Zamami

JOURNAL OF HETEROCYCLIC CHEMISTRY 49 ( 6 ) 1323 - 1331 2012年11月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

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

Polycyclic N-Heterocyclic Compounds, Part 71: Synthesis and Bronchodilator Evaluation of 5-Substituted 1,2-Dihydrofuro[3,2-f][1,7]naphthyridines and Related Compounds

Kensuke Okuda, Tetsuo Matsushita, Takashi Hirota, Kenji Sasaki

JOURNAL OF HETEROCYCLIC CHEMISTRY 49 ( 4 ) 742 - 747 2012年7月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

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

Synthesis and antimalarial activity of calothrixins A and B, and their N-alkyl derivatives

Kohji Matsumoto, Tominari Choshi, Mai Hourai, Yoshito Zamami, Kenji Sasaki, Takumi Abe, Minoru Ishikura, Noriyuki Hatae, Tatsunori Iwamura, Shigeo Tohyama, Junko Nobuhiro, Satoshi Hibino

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 22 ( 14 ) 4762 - 4764 2012年7月

記述言語：英語出版者・発行元：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

Polycyclic N-Heterocyclic Compounds, Part 69: Synthesis of 5-amino-1,2-dihydro[1]benzofuro[3,2-d]furo[2,3-b]pyridines and their transformations to related compounds

Kensuke Okuda, Jun-ichi Takano, Takashi Hirota, Kenji Sasaki

JOURNAL OF HETEROCYCLIC CHEMISTRY 49 ( 2 ) 281 - 287 2012年3月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

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

Polycyclic N-heterocyclic compounds. Part 74. Rearrangement reaction of 5-amino-1,2-dihydrofuro[2,3-c]isoquinolines with α,ω-dibromoalkanes and evaluation of product bronchodilator activity

Kensuke Okuda, Masahiko Yoshida, Takashi Hirota, Kenji Sasaki

Synthetic Communications 42 ( 6 ) 865 - 871 2012年

Quercetin diacylglycoside analogues showing dual inhibition of DNA gyrase and topoisomerase IV as novel antibacterial agents （共著）

「Hossion Abugafar M, L」「Zamami Yoshito」「Kandahary Rafiya K」「Tsuchiya Tomofusa」「Ogawa Wakano」「Iwado Akimasa」「Sasaki Kenji」

Journal of Medicinal Chemistry 54 ( 11 ) 3686 - 3703 2011年6月

Polycyclic N-heterocyclic compounds. Part 70: synthesis of 5-amino-1,2-dihydrofuro[2,3-b]pyrido[3',2':4,5]-thieno[3,2-d]pyridines and related compounds. Evaluation of effects on lipoprotein lipase mRNA expression （共著）

Heterocycles 83 ( 6 ) 1315 - 1328 2011年6月

Polycyclic N-heterocyclic compounds. Part 66: Synthesis of N-[2-([1,2,4]oxadiazol-5-yl)cyclopenten-1-yl]formamide oximes and their evaluation as inhibitors of platelet aggregation （共著）

「Okuda, Kensuke, 」「Zhang, Ying-Xue」「Ohtomo, Hiromi」「Hirota, Takashi」「Sasaki, Kenji」

Journal of Heterocyclic Chemistry 48 ( 3 ) 715 - 719 2011年5月

Polycyclic N-Heterocyclic Compounds, Part 68: Reactions of 3-(2-Bromoethyl)quinazolin-4(3H)-one and 3-(2-Bromoethyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one with Primary Alkylamines via a Dimroth-Type Rearrangement

Kensuke Okuda, Hiromi Ohtomo, Tsuyoshi Tagata, Takashi Hirota, Kenji Sasaki

SYNTHETIC COMMUNICATIONS 41 ( 6 ) 812 - 819 2011年

記述言語：英語出版者・発行元：TAYLOR & FRANCIS INC

[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

7-Chloro-1,2-dihydrofuro[2,3-c]isoquinolin-5-amine

Kensuke Okuda, Takashi Hirota, Kenji Sasaki, Hiroyuki Ishida

ACTA CRYSTALLOGRAPHICA SECTION E-STRUCTURE REPORTS ONLINE 66 ( 11 ) O2949 - U1351 2010年11月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

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

Design, synthesis, and biological evaluation of a novel series of quercetin diacylglucosides as potent anti-MRSA and anti-VRE agents （共著）

「Hossion Abugafar M L」「Otsuka Nao」「Kandahary, Rafiya K」「Tsuchiya Tomofusa」「Ogawa Wakano」「Iwado Akimasa」「Zamami Yoshito」「Sasaki Kenji」

Bioorganic & Medicinal Chemistry Letters 20 ( 17 ) 5349 - 5352 2010年9月

Polycyclic N-Heterocyclic Compounds. Part 64: Synthesis of 5-Amino-1,2,6,7-tetrahydrobenzo[f]furo[2,3-c]isoquinolines and Related Compounds. Evaluation of Their Bronchodilator Activity and Effects on Lipoprotein Lipase mRNA Expression

Kensuke Okuda, Hiroshi Deguchi, Setsuo Kashino, Takashi Hirota, Kenji Sasaki

CHEMICAL & PHARMACEUTICAL BULLETIN 58 ( 5 ) 685 - 689 2010年5月

記述言語：英語出版者・発行元：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

Polycyclic N-Heterocyclic Compounds. Part 65: Ring Cleavage Reactions of Fused Furo[2,3-c]isoquinolines and Related Compounds with Various Nucleophiles

Kensuke Okuda, Hiroshi Deguchi, Takashi Hirota, Kenji Sasaki

CHEMICAL & PHARMACEUTICAL BULLETIN 58 ( 5 ) 755 - 757 2010年5月

Polycyclic N-Heterocyclic Compounds. Part 62: Reaction of N-(Quinazolin-4-yl)amidine Derivatives with Hydroxylamine Hydrochloride and Anti-platelet Aggregation Activity of the Products

Kensuke Okuda, Ying-Xue Zhang, Hiromi Ohtomo, Takashi Hirota, Kenji Sasaki

CHEMICAL & PHARMACEUTICAL BULLETIN 58 ( 3 ) 369 - 374 2010年3月

記述言語：英語出版者・発行元：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

Polycyclic N-Heterocyclic Compounds. Part 63 Improved Synthesis of 5-Amino-1,2-dihydrofuro[2,3-c]isoquinolines via Truce-Smiles Rearrangement and Subsequent Formation to Furo[2,3-c]isoquinoline

Kensuke Okuda, Masahiko Yoshida, Takashi Hirota, Kenji Sasaki

CHEMICAL & PHARMACEUTICAL BULLETIN 58 ( 3 ) 363 - 368 2010年3月

記述言語：英語出版者・発行元：PHARMACEUTICAL SOC JAPAN

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

Polycyclic N-heterocyclic compounds. Part 61: A novel Truce-Smiles type rearrangement reaction of 4-(2-cyanovinyloxy)butanenitriles to give cycloalkeno[1,2-d]furo[2,3-b]pyridines

Kensuke Okuda, Norimasa Watanabe, Takashi Hirota, Kenji Sasaki

TETRAHEDRON LETTERS 51 ( 6 ) 903 - 906 2010年2月

記述言語：英語出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

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

Polycyclic N-Heterocyclic Compounds. Part 60: Reactions of 3-(2-Cyanophenyl)quinazolin-4(3H)-ones with Primary Amines

Kensuke Okuda, Tsuyoshi Tagata, Setsuo Kashino, Takashi Hirota, Kenji Sasaki

CHEMICAL & PHARMACEUTICAL BULLETIN 57 ( 11 ) 1296 - 1299 2009年11月

記述言語：英語出版者・発行元：PHARMACEUTICAL SOC JAPAN

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

Polycyclic N-Heterocyclic Compounds. Part 59(1)): Rearrangement Reactions of Fused Tricyclic 3-(2-Bromoethyl)pyrimidin-4(3H)-ones with Primary Amines via a Dimroth-Type Rearrangement

Kensuke Okuda, Hiromi Ohtomo, Fumiaki Tanaka, Takashi Hirota, Kenji Sasaki

CHEMICAL & PHARMACEUTICAL BULLETIN 57 ( 7 ) 755 - 758 2009年7月

記述言語：英語出版者・発行元：PHARMACEUTICAL SOC JAPAN

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

Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity

Ken-ichi Morishita, Nobumasa Yakushiji, Fuminori Ohsawa, Kayo Takamatsu, Nobuyasu Matsuura, Makoto Makishima, Masatoshi Kawahata, Kentaro Yamaguchi, Akihiro Tai, Kenji Sasaki, Hiroki Kakuta

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 19 ( 3 ) 1001 - 1003 2009年2月

記述言語：英語出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

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

Effect of the Oral Absorption Benzenesulfonanilide-Type Cyclooxygenase-1 Inhibitors on Analgesic Action and Gastric Ulcer Formation

Xiaoxia Zheng, Hiroyuki Oda, Shun Harada, Yukio Sugimoto, Akihiro Tai, Kenji Sasaki, Hiroki Kakuta

JOURNAL OF PHARMACEUTICAL SCIENCES 97 ( 12 ) 5446 - 5452 2008年12月

記述言語：英語出版者・発行元：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

Pyridinium cationic-dimer antimalarials, unlike chloroquine, act selectively between the schizont stage and the ring stage of Plasmodium falciparum

Mai Yoshikawa, Kazunori Motoshima, Kanji Fujimoto, Akihiro Tai, Hiroki Kakuta, Kenji Sasaki

BIOORGANIC & MEDICINAL CHEMISTRY 16 ( 11 ) 6027 - 6033 2008年6月

記述言語：英語出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

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

Design and synthesis of benzenesulfonanilides active against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus

Kensuke Namba, Xiaoxia Zheng, Kazunori Motoshima, Hidetomo Kobayashi, Akihiro Tai, Eizo Takahashi, Kenji Sasaki, Keinosuke Okamoto, Hiroki Kakuta

BIOORGANIC & MEDICINAL CHEMISTRY 16 ( 11 ) 6131 - 6144 2008年6月

記述言語：英語出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

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

The first potent subtype-selective retinoid X receptor (RXR) agonist possessing a 3-isopropoxy-4-isopropylphenylamino moiety, NEt-3IP (RXR alpha/beta-dual agonist)

Kayo Takamatsu, Atsushi Takano, Nobumasa Yakushiji, Kazunori Morohashi, Kenichi Morishita, Nobuyasu Matsuura, Makoto Makishima, Akihiro Tai, Kenji Sasaki, Hiroki Kakuta

CHEMMEDCHEM 3 ( 5 ) 780 - 787 2008年5月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

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

Cyclooxygenase-1-selective inhibitors are attractive candidates for analgesics that do not cause gastric damage. design and in vitro/in vivo evaluation of a benzamide-type cyclooxygenase-1 selective inhibitor

Hiroki Kakuta, Xiaoxia Zheng, Hiroyuki Oda, Shun Harada, Yukio Sugimoto, Kenji Sasaki, Akihiro Tai

JOURNAL OF MEDICINAL CHEMISTRY 51 ( 8 ) 2400 - 2411 2008年4月

記述言語：英語出版者・発行元：AMER CHEMICAL SOC

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

Reduction of lipophilicity at the lipophilic domain of RXR agonists enables production of subtype preference: RXR alpha-preferential agonist possessing a sulfonamide moiety

Kayo Takamatsu, Atsushi Takano, Nobumasa Yakushiji, Ken-ichi Morishita, Nobuyasu Matsuura, Makoto Makishima, Hamed Ismail Ali, Eiichi Akaho, Akihiro Tai, Kenji Sasaki, Hiroki Kakuta

CHEMMEDCHEM 3 ( 3 ) 454 - 460 2008年3月

記述言語：英語出版者・発行元：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

Polycyclic N-heterocyclic compounds. Part 58: Rearrangement reactions of fused 3-(2-bromoethyl)pyrimidin-4(3H)-ones with primary amines and antidepressive evaluation of the products

Hiromi Ohtomo, Tsuyoshi Tagata, Kenji Sasaki, Takashi Hirota, Kensuke Okuda

TETRAHEDRON 63 ( 51 ) 12541 - 12546 2007年12月

記述言語：英語出版者・発行元：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

Antimalarial cation-dimers synthesized in two steps from an inexpensive starting material, isonicotinic acid

Kazunori Motoshima, Yoshiko Hiwasa, Mai Yoshikawa, Kanji Fujimoto, Akihiro Tai, Hiroki Kakuta, Kenji Sasaki

CHEMMEDCHEM 2 ( 10 ) 1527 - 1532 2007年10月

記述言語：英語出版者・発行元：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

Analgesic agents without gastric damage: Design and synthesis of structurally simple benzenesulfonanilide-type cyclooxygenase-1-selective inhibitors

Xiaoxia Zheng, Hiroyuki Oda, Kayo Takamatsu, Yukio Sugimoto, Akihiro Tai, Eiichi Akaho, Hamed Ismail Ali, Toshiyuki Oshiki, Hiroki Kakuta, Kenji Sasaki

BIOORGANIC & MEDICINAL CHEMISTRY 15 ( 2 ) 1014 - 1021 2007年1月

記述言語：英語出版者・発行元：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

Antimalarial effect of bis-pyridinium salts, N,N '-hexamethylenebis(4-carbamoyl-1-alkylpyridinium bromide)

K Fujimoto, D Morisaki, M Yoshida, T Namba, K Hye-Sook, Y Wataya, H Kourai, H Kakuta, K Sasaki

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 16 ( 10 ) 2758 - 2760 2006年5月

記述言語：英語出版者・発行元：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

Involvement of intracellular Ca2+ levels in nonsteroidal anti-inflammatory drug-induced apoptosis

Ken-Ichiro Tanaka, Wataru Tomisato, Tatsuya Hoshino, Tomoaki Ishihara, Takushi Namba, Mayuko Aburaya, Takashi Katsu, Keitarou Suzuki, Shinji Tsutsumi, Tohru Mizushima

Journal of Biological Chemistry 280 ( 35 ) 31059 - 31067 2005年9月

記述言語：英語

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

Transition-metal-catalyzed rearrangement of 5-alkynals to gamma-alkynylketones and 1-cyclopentenylketones

K Tanaka, K Sasaki, K Takeishi, K Sugishima

CHEMICAL COMMUNICATIONS ( 37 ) 4711 - 4713 2005年

Membrane permeabilization by non-steroidal anti-inflammatory drugs

W Tomisato, K Tanaka, T Katsu, H Kakuta, K Sasaki, S Tsutsumi, T Hoshino, M Aburaya, DW Li, T Tsuchiya, K Suzuki, K Yokomizo, T Mizushima

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 323 ( 3 ) 1032 - 1039 2004年10月

記述言語：英語出版者・発行元：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

The synthesis of (±)-monomorine I starting with the palladium-catalyzed carbonylative 1,4-acylation of an organozinc chloride

Motoki Yuguchi, Masao Tokuda, Kenji Sasaki, Kazuhiko Orito

Bulletin of the Chemical Society of Japan 77 ( 5 ) 1031 - 1032 2004年5月

Winter cherry bugs feed on plant tropane alkaloids and de-epoxidize scopolamine to atropine.

Yoshie Kitamura, Yoshinori Tominaga, Kenji Sasaki, Toshihiko Ikenaga

Journal of Chemical Ecology 2004年

Synthesis of febrifugine derivatives and a solution to the puzzle of the structural determination of febrifugine

Y Takeuchi, K Azuma, M Oshige, H Abe, H Nishioka, K Sasaki, T Harayama

TETRAHEDRON 59 ( 10 ) 1639 - 1646 2003年3月

記述言語：英語出版者・発行元：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

Transglucosylation activities of multiple forms of α-glucosidase from spinach

Sugimoto, Manabu, Furui, Satoshi, Sasaki, Kenji, Suzuki, Yukio

Bioscience, Biotechnology, and Biochemistry 67 ( 5 ) 1160 - 1163 2003年1月

Synthesis and Characterization of 6-O-Acyl-2-O-a-D-Glucopyranosyl-L-ascorbic Acids with a Branched-acyl Chain

Akihiro Tai, Daisuke Kawasaki, Kenji Sasaki, Eiichi Gohda, Itaru Yamamoto

Chemical and Pharmaceutical Bulletin 2003年

Synthesis and characterization of a series of novel monoacylated ascorbic acid derivatives, 6-O-acyl-2-O-alpha-D-glucopyranosyl-L-ascorbic acids, as skin antioxidants

Yamamoto, I, A Tai, Y Fujinami, K Sasaki, S Okazaki

JOURNAL OF MEDICINAL CHEMISTRY 45 ( 2 ) 462 - 468 2002年1月

記述言語：英語出版者・発行元：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

Synthesis and Characterization of a Series of Novel Monoacylated Ascorbic Acid Derivatives, 6-O-Acyl-2-O-a-D-glucopyranosyl-L-ascorbic Acids, as Skin Antioxidants.

Itaru Yamamoto, Akihiro Tai, Yoshihito Fujinami, Kenji Sasaki, Shino Okazaki

J. Med. Chem. 2002年

Synthesis of Methylthiomaleimides for the Preparation of Pyridazines and Related Compound

Yoshinori Tominaga, Yasuhiro Shigemitsu, Kenji Sasaki

J. Heterocyclic Chem. 2002年

Synthesis of methylthiomaleimides for the preparation of pyridazines and related compounds

Yoshinori Tominaga, Yasuhiro Shigemitsu, Kenji Sasaki

Journal of Heterocyclic Chemistry 39 ( 3 ) 571 - 591 2002年

記述言語：英語出版者・発行元：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

Study on Glutathionesulfonic Acid Sodium Salt as Biodistribution Promoter for Thiopental Sodium

Yuhsuke Ohkawa, Tomonori Fujimoto, Kyohko Higashiyama, Hiroshi Maeda, Tomoyuki Asoh, Masateru Kurumi, Kenji Sasaki, Taiji Nakayama

Biological and Pharmaceutical Bulletin 2002年

Re-revision of the Stereo Structure of Piperidine Lactone, an Intermediate in the Synthesis of Febrifugine

Yasuo Takeuchi, Kumiko Azuma, Hiroshi Abe, Kenji Sasaki, Takasi Harayama

Chemical and Pharmaceutical Bulletin 2002年

A new dipeptide, O-phosphoserylethanolamine isolated from Agkistroden blomhoffi (mamushi)

Noriyoshi Masuoka, Jianying Zhang, Leila Partoo, Jun Ohta, Kenji Sasaki, Hideo Ebinuma, Hiroyuki Kodama

Archives of Biochemistry and Biophysics 2002年

Polycyclic N-Heterocyclic Compounds. 56. Reaction of N-(5,6-Dihydro[1]benzoxepino-[5,4-d]pyrimidin-4-yl)amidine or Its Amide Oxime Derivatives with Hydroxyl-amine Hyrdochloride

Kenji Sasaki, Ying-Xue Zhang, Kensuke Okuda, Takashi Hirota

J. Heterocyclic Chem. 2001年

Effects of 4-Hydroxyantipyrine and Acetaminophen O-Sulfate as Biodistribution Promoter

Yuhsuke Ohkawa, Yasunori Kiyohara, Tomoyuki Asoh, Hiroshi Maeda, Masateru Kurumi, Kenji Sasaki, Yuhji Kurosaki, Miki Matsumura, Taiji Nakayama

Biol. Pharm. Bull. 2001年

Effects of 4-Hydroxyantipyrine and Its 4-O-Sulfate on Antipyrine as Biodistribution Promoter

Yusuke Ohkawa, Miki Matsumura, Yuhji Kurosaki, Masateru Kurumi, Kenji Sasaki, Taiji Nakayama

Biol. Pharm. Bull. 2001年

Polycyclic N-Heterocyclic Compounds. 57. Syntheses of Fused Furo(or Thieno)[2,3-b]Pyridine Derivatives via Smiles Rearrangement and Intramolecular Cyclization

Takashi Hirota, Kei-ichiroh Tomita, Kenji Sasaki, Kensuke Okuda, Masahiko Yoshida, Setsuo Kashino

Heterocycles 2001年

Synthesis and Chemiluminescent Activity of 8,9-Dihydrobenzo[g]pyridazino[4,5-b]indole-7,10(11H)-diones

Masateru Kurumi, Kenji Sasaki, Hiroko Takata, Taiji Nakayama

J. Heterocyclic Chem. 2001年

Study on Glutathione-sulphonic Acid as Biodistribution Promoter: Concomitant Use Effect on Verapamil Hydrochloride and Tegafur.

Yusuke Ohkawa, Kyohko Higashiyama, Shigenari Sugaya, Tomoyuki Asoh, Hiroshi Maeda, Kenji Sasaki, Taiji Nakayama

Biol. Pharm. Bull. 2001年

Syntheses of Thiopyrone and Pyrone Derivatives by Photocyclization Reaction of 3-Aryl-2-([1]benzothien-3-yl)-propenoic Acids

Kenji Sasaki, Yasuyoshi Satoh, Takashi Hirota, Taiji Nakayama, Yoshinori Tominaga, nd Raymo, N. Castle

J. Heterocyclic Chem. 2000年

Synthesis and Chemiluminescent Activity of Pyridazino[4,5-b]indole-1,4- (2H,3H)-diones

Masateru Kurumi, Kenji Sasaki, Hiroko Takata, Taiji Nakayama

Heterocycles 2000年

Syntheses of thiopyrone and pyrone derivatives by photocyclization reaction of 3-aryl-2-([1]benzothien-3-yl)propenoic acids

Kenji Sasaki, Yasuyoshi Satoh, Takashi Hirota, Taiji Nakayama, Yoshinori Tominaga, Raymond N. Castle

Journal of Heterocyclic Chemistry 37 ( 4 ) 959 - 967 2000年

記述言語：英語

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

Biopharmaceutical Studies on Drug/Conjugated Metabolites Interactions: Application of Organic Sulfonic Compounds as Biodistribution Promoters

Yuhji Kurosaki, Yuhsuke Ohkawa, Kenji Sasaki, Taiji Nakayama

Pharmazie 2000年

Synthesis and chemiluminescence of 10-hydroxy- and 10- aminopyridazino[4,5-b]quinoline-1,4(2H, 3H)-diones

Yoshinori Tominaga, Noriko Yoshioka, Seigo Kataoka, Yasuhiro Shigemitsu, Takashi Hirota, Kenji Sasaki

Heterocycles 50 ( 1 ) 43 - 46 1999年1月

記述言語：英語出版者・発行元：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

A novel reaction of N-(5,6-dihydro[1]benzothiepino[5,4-d]pyrimidin-4-yl)amidine or its amide oxime derivatives with hydroxylamine(共著)

Journal of Heterocyclic Chemistry 36 ( 3 ) 787 - 791 1999年

Polycyclic N-heterocyclic compounds. 55 [1]. A novel reaction of N- (5,6-dihydro[1]benzothiepino[5,4-d]pyrimidin-4-yl)amidine or its amide oxime derivatives with hydroxylamine

Ying-Xue Zhang, Kenji Sasaki, Takashi Hirota

Journal of Heterocyclic Chemistry 36 ( 3 ) 787 - 791 1999年

記述言語：英語出版者・発行元：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

Polycyclic N-Heterocyclic Compounds. 55. A novel reaction of N-(5,6-dihydro[1]benzothiepino[5,4-d]pyrimidin-4-yl)amidine or its amide oxime derivatives with hydroxylamine

Ying-Xue Zhang, Kenji Sasakii, Takashi Hirota

Journal of Heterocyclic Chemistry 1999年

Synthesis and pharmacological evaluation of 2,3,6,7-tetrahydrothieno[2,3-h]imidazo-[2,1-f][1,6]naphthyridines, 3,4,7,8-tetrahydro-2H-thieno[2,3-h]pyrimido[2,1-f][1,6]-naphthyridines and their precursor(共著)

Journal of Heterocyclic Chemistry 36 ( 2 ) 461 - 465 1999年

Polycyclic N-heterocyclic compounds. 50 [1]. Synthesis and pharmacological evaluation of 2,3,6,7-tetrahydrothieno[2,3-h]- imidazo[2,1 - f] [1,6] naphthyridines, 3,4,7,8-tetrahydro-2H-thieno[2,3-h]pyrimido[2,1- f][1,6]naphthyridines and their precursor

Kenji Sasaki, Abu Shara S. Rouf, Takashi Hirota, Naoki Nakaya

Journal of Heterocyclic Chemistry 36 ( 2 ) 461 - 465 1999年

記述言語：英語出版者・発行元：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

Synthesis and pharmacological evaluation of 2,3,6,7-tetrahydrothieno[2,3-h]imidazo[2,1- f][1,6]naphthyridines, 3,4,7,8-tetrahydro-2H-thieno[2,3-h]pyrimido[2,1- f][1,6]naphthyridines and their precursor

Kenji Sasaki, Abu Shara, Shamusur Rouf, Naoki Nakaya, Takashi Hirota

Journal of Heterocyclic Chemistry 1999年

Ring-cleavages and ring-closures of N-(benzo[h]quinazolin-4-yl)amidine and its amide oxime derivatives with hydroxylamine

Kenji Sasaki, Ying-Xue Zhang, Hiroshi Yamamoto, Setsuo Kashino, Takashi Hirota

Journal of Chemical Research (M) 1999年

Ring-cleavages and ring-closures of N-(benzo[h]quinazolin-4-yl)amidine and its amide oxime derivatives with hydroxylamine(共著)

Journal of Chemical Research(S) ( 2 ) 92 - 93 1999年

Polycyclic N-heterocyclic compounds. Part 54. Ring-cleavages and ring- closures of N-(benzo[h]quinazolin-4-yl)amidine and its amide oxime derivatives with hydroxylamine

Kenji Sasaki, Ying-Xue Zhang, Hiroshi Yamamoto, Setsuo Kashino, Takashi Hirota

Journal of Chemical Research - Part S ( 2 ) 92 - 93 1999年

記述言語：英語出版者・発行元：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

Ring-cleavages and ring-closures of N-(benzo[h]quinazolin-4-yl)amidine and its amide oxime derivatives with hydroxylamine

Kenji Sasaki, Ying-Xue Zhang, Hiroshi Yamamoto, Setsuo Kashino, Takashi Hirota

Journal of Chemical Research (S) 1999年

Synthesis and chemiluminescence of 10-hydroxy- and 10-aminopyridazino[4,5-b]quinoline-1,4(2H,3H)-diones

Yoshinori Tominaga, Noriko Yoshioka, Seigo Kataoka, Yasuhiro Shigemitsu, Takashi Hirota, Kenji Sasaki

Heterocycles 1999年

Polycyclic N-Heterocyclic Compounds. 53 One Step Syntheses of Imidazo[1,5-a]pyridine Derivatives by The Vilsmeier Reaction Using N,N-Dimethylarylamides

Kenji Sasaki, Akifumi Tsurumori, Setsuo Kashino, Takashi Hirota

Heterocycles 1999年

Biopharmaceutical Studies on Drug/Conjugated-Metabolite Interactions. III. Effect of Acetaminophen Sulfate and Its Positional Isomers on the Pharmacokinetics of Acetaminophen in Rats (共著)

Nakayama Taiji, Sawamoto Taiji, Karino Tadaaki, MATSUMURA Miki, SASAKI Kenji, KUROSAKI Yuji, KIMURA Toshikiro

Biological Pharmaceutical Bulletin 20 ( 5 ) 522 - 529 1997年5月

記述言語：英語出版者・発行元：公益社団法人日本薬学会

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

その他リンク： https://jlc.jst.go.jp/DN/JALC/00083788598?from=CiNii

Biopharmaceutical Studies on Drug/Conjugated-Metabolite Interactions. III. Effect of Acetaminophen Sulfate and Its Positional Isomers on the Pharmacokinetics of Acetaminophen in Rats

Nakayama Taiji, Sawamoto Taiji, Karino Tadaaki, MATSUMURA Miki, SASAKI Kenji, KUROSAKI Yuji, KIMURA Toshikiro

Biological & pharmaceutical bulletin 20 ( 5 ) 522 - 529 1997年5月

記述言語：英語出版者・発行元：公益社団法人日本薬学会

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

その他リンク： https://jlc.jst.go.jp/DN/JALC/00083788598?from=CiNii

Biopharmaceutical studies on drug/conjugated-metabolite interactions. II. Effect of acetaminophen sulfate on pharmacokinetics of acetaminophen in rats

Taiji Sawamoto, Yuji Kurosaki, Kenji Sasaki, Toshikiro Kimura, Taiji Nakayama

International Journal of Pharmaceutics 146 ( 2 ) 181 - 191 1997年1月

記述言語：英語

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

Biopharmaceutical Studies on Drug/Conjugated-Metabolite Interactions. II. Effect of Acetaminophen Sulfate on Pharmacokinetics of Acetaminophen in Rats (共著)

International Journal of Pharmaceutics 146 ( 2 ) 181 - 191 1997年1月

Synthesis of new methine class of dyes bearing maleimide ring system

Yoshinori Tominaga, Kaori Komiya, Sachiko Itonaga, Noriko Yoshioka, Seigo Kataoka, Kenji Sasaki, Takashi Hirota

Heterocycles 46 ( 1 ) 41 - 44 1997年

記述言語：英語出版者・発行元：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

Synthesis of New Methine Class of Dyes Bearing Maleimide Ring System. (共著)

Heterocycles 46 ( 1 ) 41 - 44 1997年

Isolation and characterization of N-acetyl-S-[2-carboxy-1-(1H-imidazol-4-yl) ethyl]-L-cysteine, a new metabolite of histidine, from normal human urine and its formation from S-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]-L-cysteine

Masahiro Kinuta, Kenji Sasaki, Hiroo Shimizu, Toshihiko Ubuka

Biochimica et Biophysica Acta - General Subjects 1291 ( 2 ) 131 - 137 1996年10月

記述言語：英語出版者・発行元：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

Isolation and Characterization of N-Acetyl-S-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]-L-cysteine, A New Metabolite of Histidine, from Normal Human Urine and Its Formation from S-[2-Carboxy-1-(1H-imidazol-4-yl)ethyl]-L-cysteine. (共著)

Biochimica et Biophysica Acta 1291 ( 2 ) 131 - 137 1996年10月

Synthesis of Novel 12-Substituted11,13,15-Triazasteroidal Compounds and Their Inhibitory Activity on Platelet Aggregation. (共著)

Journal of Heterocyclic Chemistry 33 ( 6 ) 1663 - 1669 1996年

The Synthesis of Novel Polycyclic Heterocyclic Ring Systems. 2. Naphtho-[2,1-b : 4,3-g]bisbenzo[b]thiophene. (共著)

Journal of Heterocyclic Chemistry 33 ( 3 ) 847 - 853 1996年

Polycyclic N-heterocyclic compounds. 51. Synthesis of novel 12-substituted 11,13,15-triazasteroidal compounds and their inhibitory activity on platelet aggregation

Kenji Sasaki, Takeshi Arichi, Hiromi Ohtomo, Taiji Nakayama, Takashi Hirota

Journal of Heterocyclic Chemistry 33 ( 6 ) 1663 - 1669 1996年

記述言語：英語出版者・発行元：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

The synthesis of novel polycyclic heterocyclic ring systems. 2. Naphtho[2,1-b:4,3-g]bisbenzo[b]thiophene

Kenji Sasaki, Osamu Tokuda, Takashi Hirota, Jiann-Kuan Luo, Raymond N. Castle

Journal of Heterocyclic Chemistry 33 ( 3 ) 847 - 853 1996年

記述言語：英語出版者・発行元：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

Synthesis of Thieno [2, 3-DB<h>(/)-DB] [1,6] naphthyridine from 2-(3-Cyanopropylthio) pyridine-3-carbonitrile : Formation of a novel Ring System (共著)

Journal of The Chemical Society, Chemical Communication ( 15 ) 1767 - 1768 1994年

Synthesis of thieno[2,3-h][1,6]naphthyridine from 2-(3-cyanopropylthio) pyridine-3-carbonitrile: Formation of a novel ring system

Kenji Sasaki, Rouf A. S. Shamsur, Setsuo Kashino, Takashi Hirota

Journal of the Chemical Society, Chemical Communications ( 15 ) 1767 - 1768 1994年

Polycyclic DB<N>(/)-DB-Heterocyclic Compounds. XLV. Synthesis of the Nove1 B,D-Dihomo-11,13,15-tri--azasteroidal Skeleton and their Effect on Reserpine-Induced Hypothermia and Inhibitory Activity on Platelet Aggregation (共著)

Journal of Heterocyclic Chemistry 30 ( 4 ) 989 - 992 1993年

Polycyclic N‐heterocyclic compounds. XLIV. Synthesis of the novel B,D‐Dihomo‐11,13,15‐triazasteroidal skeleton and their effect on reserpine‐induced hypothermia and inhibitory activity on platelet aggregation

Kenji Sasaki, Yuichi Arimoto, Hiromi Ohtomo, Taiji Nakayama, Takashi Hirota

Journal of Heterocyclic Chemistry 30 ( 4 ) 989 - 992 1993年

記述言語：英語

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

Polycyclic (]E8BAA[)-Hetero Compounds. XXXVI. Syntheses and Antidepressive Evaluation of 11,13,15,17-Tetraazasteroids and Their 17-Oxides. (共著)

Journal of Heterocyclic Chemistry 28 ( 2 ) 257 - 261 1991年

Polycyclic N‐hetero compounds. XXXVI. Syntheses and antidepressive evaluation of 11,13,15,17‐tetraazasteroids and their 17‐oxides

Takashi Hirota, Kenji Sasaki, Hiroshi Yamamoto, Taiji Nakayama

Journal of Heterocyclic Chemistry 28 ( 2 ) 257 - 261 1991年

Polycyclic (]E8BAA[)-Hetero Compounds. XXXII. Synthesis and Antidepressive Evaluation of B-Homo-11,13,15-triazasteroids and Their Precursors. (共著)

Journal of Heterocyclic Chemistry 27 ( 3 ) 759 - 763 1990年

Polycyclic N‐hetero compounds. XXXII Synthesis and antidepressive evaluation of B‐homo‐11,13,15‐triazasteroids and their precursors

Takashi Hirota, Kenji Sasaki, Katsuhiro Ieno, Yuhki Sekiya, Taiji Nakayama

Journal of Heterocyclic Chemistry 27 ( 3 ) 759 - 763 1990年

Polycyclic (]E8BAA[)-Hetero Compounds. XXIX. Synthesis and Antidepressive Evaluation of 15-Thia-11,13-diazasteroidal Analogues and Their Precursors. (共著)

Journal of Heterocyclic Chemistry 24 ( 2 ) 341 - 344 1987年

Polycyclic N‐hetero compounds. XXIX. Synthesis and antidepressive evaluation of 15‐thia‐11,13‐diazasteroidal analogues and their precursors

Takashi Hirota, Rieko Hamazaki, Takako Ohdoi, Kenji Sasaki, Tetsuto Namba

Journal of Heterocyclic Chemistry 24 ( 2 ) 341 - 344 1987年

記述言語：英語

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

Polycyclic N‐hetero compounds. XXVII. Synthesis and investigation of the antidepressive activity of a B‐Homo‐11,13,15‐triazasteroid and its related compoundsd

Takashi Hirota, Katsuhiro Ieno, Kenji Sasaki

Journal of Heterocyclic Chemistry 23 ( 6 ) 1685 - 1687 1986年

A Novel Synthesis of Benzofuran and Related Compounds. III. The Vilsmeier Reaction of Phenoxyacetaldehyde Diethyl Acetals. (共著)

Jounral of Heterocyclic Chemistry 23 ( 6 ) 1715 - 1716 1986年

A Novel Synthesis of Benzofuran and Related Compounds. I. The Vilsmeier Reaction of Phenoxyacetonitriles. (共著)

Jounral of Heterocyclic Chemistry 23 ( 5 ) 1347 - 1351 1986年

A novel synthesis of benzofuran and related compounds. III. The vilsmeier reaction of phenoxyacetaldehyde diethyl acetals

Takashi Hirota, Hiroko Fujita, Kenji Sasaki, Tetsuto Namba

Journal of Heterocyclic Chemistry 23 ( 6 ) 1715 - 1716 1986年

Polycyclic (]E8BAA[)-Hetero Compounds. XXVII. Synthesis and Investigation of the Antidepressive Activity of a B-Homo-11,13,15-triazasteroid and Its Related Compounds. (共著)

Journal of Heterocyclic Chemistry 23 ( 6 ) 1685 - 1687 1986年

A novel synthesis of benzofuran and related compounds. I. The vilsmeier reaction of phenoxyacetonitriles

Takashi Hirota, Hiroko Fujita, Kenji Sasaki, Tetsuto Namba, And Shohei Hayakawa

Journal of Heterocyclic Chemistry 23 ( 5 ) 1347 - 1351 1986年

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