著者

安本 三治 山下 純一 橋本 貞夫

出版者

公益社団法人日本薬学会

雑誌

藥學雜誌 (ISSN:00316903)

巻号頁・発行日

vol.98, no.11, pp.1551-1553, 1978-11-25

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Synthesis of 3-(tetrahydro-2-furanyl)-5-fluorouracil (3-Thf-FU) (III), which has been found to be a metabolic intermediate of 1,3-bis (tetrahydro-2-furanyl)-5-fluorouracil (Thf_2-FU) and an effective antitumor agent, is reported. 1-Alkane- or 1-arene-sulfonyl-5-fluorouracil (I) was trimethylsilylated by treatment with N, O-bis (trimethylsilyl) acetamide and treated with 2-acetoxytetrahydrofuran in the presence of stannic chloride to give 1-alkane- or 1-arene-sulfonyl-3-(tetrahydro-2-furanyl)-5-fluorouracil (II). III was obtained by deblocking of II with methanolic ammonia.

著者

上田 修一 武田 節夫 山脇 一郎 山下 純一 安本 三治 橋本 貞夫

出版者

公益社団法人日本薬学会

雑誌

CHEMICAL & PHARMACEUTICAL BULLETIN (ISSN:00092363)

巻号頁・発行日

vol.30, no.1, pp.125-131, 1982

被引用文献数

8

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A hydroxylated metabolite of 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT), 1-(trans-3-hydroxytetrahydro-2-furanyl)-5-fluorouracil (trans-3'-OH-FT, VIII) and its isomer, 1-(cis-3-hydroxytetrahydro-2-furanyl)-5-fluorouracil (cis-3'-OH-FT, VI), were synthesized and isolated at high purity. As compounds related to FT metabolites, 2, 3'-anhydro-1-(cis-3-hydroxytetrahydro-2-furanyl)-5-fluorouracil (2, 3'-anhydro-FT, V), 1-(2, 5-dihydro-2-furanyl)-5-fluorouracil (3', 4'-dehydro-FT, XII) and 1-(5-acetoxytetrahydro-2-furanyl)-5-fluorouracil (5'-AcO-FT, XI) were also synthesized. The antitumor activities of these compounds against sarcoma 180 and L 1210 were examined. The activities of cis-3'-OH-FT (VI) and 2, 3'-anhydro-FT (V) were found to be lower than that of FT. The activity of 5'-AcO-FT (XI) was the same as that of FT. 3', 4'-Dehydro-FT (XII) showed much greater activity than FT.

著者

山下 純一 山脇 一郎 上田 修一 安本 三治 采見 憲男 橋本 貞夫

出版者

公益社団法人日本薬学会

雑誌

Chemical & pharmaceutical bulletin (ISSN:00092363)

巻号頁・発行日

vol.30, no.12, pp.4258-4267, 1982-12-25

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Six types of 5-fluorouracil (5-FU) derivatives were synthesized ; namely, 2,4-di-O-substituted, 2-O-substituted, 4-O-substituted, 1,3-disubstituted, 1-substituted and 3-substituted compounds. After oral administration of these compounds to rats, the blood levels of 5-FU were determined. Among O-substituted derivatives, a 4-O-substituted derivative was most easily activated to 5-FU and 2-O-substituted derivatives were next most easily activated. Among N-substituted derivatives, acyl and sulfonyl derivatives showed the highest 5-FU releasing abilities and 1-alkoxymethyl substituted derivatives showed low ability. N-Alkyl substituted derivatives were not activated to 5-FU. Several compounds which gave higher blood levels of 5-FU than that obtained with 1-(tetrahydro-2-furyl)-5-fluorouracil (Thf-FU), as well as same related compounds, were selected and their antitumor activities were examined. The 2-O-substituted derivatives, 2-butoxy-5-fluoro-4 (1H)-pyrimidone (11) and 2-benzyloxy-5-fluoro-4 (1H)-pyrimidone (19), were as effective as Thf-FU. The activities of 2,4-di-O-substituted derivatives, 2,4-dibutoxy-5-fluoropyrimidine (1) and 2,4-dibenzyloxy-5-fluoropyrimidine (6), against Ehrlich carcinoma and against sarcoma 180,respectively, were the same as those of Thf-FU. The 1-substituted derivatives, 1-ethoxymethyl-5-fluorouracil (49) and 1-(1-ethoxy-1-phenylmethyl)-5-fluorouracil (50), were found to be as effective as Thf-FU.

著者

山下 純一 安本 三治 橋本 貞夫

出版者

公益社団法人日本薬学会

雑誌

Chemical & pharmaceutical bulletin (ISSN:00092363)

巻号頁・発行日

vol.31, no.11, pp.3872-3877, 1983-11-25

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The mechanism of the condensation of 5-fluorouracil and 2-acetoxytetrahydrofuran (3), giving 1-(tetrahydro-2-furyl)-5-fluorouracil, was studied. An equilibrium between 2-acetoxytetrahydrofuran (3) and 2,3-dihydrofuran (4) was observed at 120-170℃ in dimethylformamide. It was found by the use of 1,3-dideuterio-5-fluorouracil that the condensation of 5-fluorouracil with 3 occurred both by direct substitution and by the formation of 4 from 3 followed by addition of the uracil to it. The contribution of the latter path increased with increase of the reaction temperature.

著者

山下 純一 山脇 一郎 上田 修一 安本 三治 采見 憲男 橋本 貞夫

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.30, no.12, pp.4258-4267, 1982-12-25 (Released:2008-03-31)

参考文献数

32

被引用文献数

15 18

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Six types of 5-fluorouracil (5-FU) derivatives were synthesized ; namely, 2, 4-di-O-substituted, 2-O-substituted, 4-O-substituted, 1, 3-disubstituted, 1-substituted and 3-substituted compounds. After oral administration of these compounds to rats, the blood levels of 5-FU were determined. Among O-substituted derivatives, a 4-O-substituted derivative was most easily activated to 5-FU and 2-O-substituted derivatives were next most easily activated. Among N-substituted derivatives, acyl and sulfonyl derivatives showed the highest 5-FU releasing abilities and 1-alkoxymethyl substituted derivatives showed low ability. N-Alkyl substituted derivatives were not activated to 5-FU. Several compounds which gave higher blood levels of 5-FU than that obtained with 1-(tetrahydro-2-furyl)-5-fluorouracil (Thf-FU), as well as same related compounds, were selected and their antitumor activities were examined. The 2-O-substituted derivatives, 2-butoxy-5-fluoro-4 (1H)-pyrimidone (11) and 2-benzyloxy-5-fluoro-4 (1H)-pyrimidone (19), were as effective as Thf-FU. The activities of 2, 4-di-O-substituted derivatives, 2, 4-dibutoxy-5-fluoropyrimidine (1) and 2, 4-dibenzyloxy-5-fluoropyrimidine (6), against Ehrlich carcinoma and against sarcoma 180, respectively, were the same as those of Thf-FU. The 1-substituted derivatives, 1-ethoxymethyl-5-fluorouracil (49) and 1-(1-ethoxy-1-phenylmethyl)-5-fluorouracil (50), were found to be as effective as Thf-FU.

著者

上田 修一 武田 節夫 山脇 一郎 山下 純一 安本 三治 橋本 貞夫

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.30, no.1, pp.125-131, 1982-01-25 (Released:2008-03-31)

参考文献数

20

被引用文献数

5 8

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A hydroxylated metabolite of 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT), 1-(trans-3-hydroxytetrahydro-2-furanyl)-5-fluorouracil (trans-3'-OH-FT, VIII) and its isomer, 1-(cis-3-hydroxytetrahydro-2-furanyl)-5-fluorouracil (cis-3'-OH-FT, VI), were synthesized and isolated at high purity. As compounds related to FT metabolites, 2, 3'-anhydro-1-(cis-3-hydroxytetrahydro-2-furanyl)-5-fluorouracil (2, 3'-anhydro-FT, V), 1-(2, 5-dihydro-2-furanyl)-5-fluorouracil (3', 4'-dehydro-FT, XII) and 1-(5-acetoxytetrahydro-2-furanyl)-5-fluorouracil (5'-AcO-FT, XI) were also synthesized. The antitumor activities of these compounds against sarcoma 180 and L 1210 were examined. The activities of cis-3'-OH-FT (VI) and 2, 3'-anhydro-FT (V) were found to be lower than that of FT. The activity of 5'-AcO-FT (XI) was the same as that of FT. 3', 4'-Dehydro-FT (XII) showed much greater activity than FT.

著者

橋本 貞夫 鈴江 崇志

出版者

The Society of Synthetic Organic Chemistry, Japan

雑誌

有機合成化学協会誌 (ISSN:00379980)

巻号頁・発行日

vol.38, no.6, pp.528-537, 1980-06-01 (Released:2009-11-13)

参考文献数

33

被引用文献数

1 2

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1- (Tetrahydro-2-furanyl) -5-fluorouracil (Futraful®, FT-207) was synthesized by S.A. Hiller, et al. in 1967. In this 5-fluorouracil (5-FU) derivative, a tetrahydrofuran group replace the sugar on the nucleoside.FT-207 is an antimetabolite, anti-tumor agent, and is well absorbed from the intenstine. It is gradually metabolized to substances such as 5-FU, 5-fluorouridine (FUR) and 5-Fluorouridine monophosphate (FUMP), which exhibit anti-tumor activity. These active substances are maintained in the blood and tissues for a long time, and thus FT-207 shows significant anti-tumor activity.FT-207 has less effect than other anti-tumor agents on antibody production, the blood picture and the functions of the liver, spleen and kidney. Thus since it has only side effects, it can be used for a long-term therapeutic treatment.It is effective when given intravenously, orally or intrarectally and has been employed clinically to induce tumor regression and to maintain regression and inhibit metastases.

著者

小川 和男 寺田 忠史 村中 義幸 浜川 寿博 橋本 貞夫 藤井 節郎

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.34, no.8, pp.3252-3266, 1986-08-25 (Released:2008-03-31)

参考文献数

34

被引用文献数

3 7

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Many 2-oxoalkyl arenesulfonate derivatives having straight or branched alkyl chains of different lengths, 2-oxoalkyl bis-arenesulfonate derivatives, and alkyl arenesulfonate derivatives having a ketal moiety at the 2-position on the alkyl chain were synthesized, and their esterase-inhibitory activities, as well as hypolipidemic activities, were evaluated.Among these compounds, 1-(2, 4, 6-trimethylbenzenesulfonyloxy)-2-dodecanone (III-1u), and 1-(2, 3, 4, 6-tetramethylbenzenesulfonyloxy)-2-hexanone (III-1w), -2-octanone (III-1x) and -2-decanone (III-1y) exhibited potent esterase-inhibitory activities (IC50=3×10-10, 2×10-10, 2×10<-10> and 3×<-11>M, respectively). However, the sulfonate (XV) having a ketal moiety on the alkyl chain and the bis-sulfonate (XVI) exhibited low inhibitory activities toward esterase in comparison with III and XII. Most of the compounds III and some of the compounds XII exhibited potent hypolipidemic activities corresponding to more than 50% lipid-lowering effect (plasma triglyceride and cholesterol ester) in vivo. The structure-activity relatioinships of these compounds are discussed.

著者

小川 和男 寺田 忠史 村中 義幸 浜川 寿博 橋本 貞夫 藤井 節郎

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.34, no.3, pp.1118-1127, 1986-03-25 (Released:2008-03-31)

参考文献数

43

被引用文献数

7 7

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Many 1-substituted 2-alkanone derivatives were synthesized and their inhibitory activities toward pancreatic lipase and esterase were examined in order to obtain hypolipidemic agents. 1-Benzenesulfonyloxy-2-pentanone (VI-2a) and 1-(2, 4, 6-trimethylbenzenesulfonyloxy)-2-pentanone (VI-2q) exhibited not only potent and selective esterase inhibitions (IC50 : 9.0×10-7M and 1.0×10-6M, respectively), but also potent hypolipidemic action (90 and 92% reductions of plasma triglyceride, and 53 and 90% reductions of plasma total cholesterol, respectively). A novel working hypothesis is presented to account for the lowering of the plasma lipids level, i.e., that inhibition of esterase and lipase activities in the small intestinal lumen may be responsible for the decrease in the plasma lipids level.

著者

安本 三治 山下 純一 橋本 貞夫

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.98, no.11, pp.1551-1553, 1978-11-25 (Released:2008-05-30)

参考文献数

10

被引用文献数

6 5

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Synthesis of 3-(tetrahydro-2-furanyl)-5-fluorouracil (3-Thf-FU) (III), which has been found to be a metabolic intermediate of 1, 3-bis (tetrahydro-2-furanyl)-5-fluorouracil (Thf2-FU) and an effective antitumor agent, is reported. 1-Alkane- or 1-arene-sulfonyl-5-fluorouracil (I) was trimethylsilylated by treatment with N, O-bis (trimethylsilyl) acetamide and treated with 2-acetoxytetrahydrofuran in the presence of stannic chloride to give 1-alkane- or 1-arene-sulfonyl-3-(tetrahydro-2-furanyl)-5-fluorouracil (II). III was obtained by deblocking of II with methanolic ammonia.

著者

山下 純一 安本 三治 橋本 貞夫

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.31, no.11, pp.3872-3877, 1983-11-25 (Released:2008-03-31)

参考文献数

19

被引用文献数

3 4

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The mechanism of the condensation of 5-fluorouracil and 2-acetoxytetrahydrofuran (3), giving 1-(tetrahydro-2-furyl)-5-fluorouracil, was studied. An equilibrium between 2-acetoxytetrahydrofuran (3) and 2, 3-dihydrofuran (4) was observed at 120-170°C in dimethylformamide. It was found by the use of 1, 3-dideuterio-5-fluorouracil that the condensation of 5-fluorouracil with 3 occurred both by direct substitution and by the formation of 4 from 3 followed by addition of the uracil to it. The contribution of the latter path increased with increase of the reaction temperature.