著者

山村 初雄 藤田 佳平衛

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.39, no.10, pp.2505-2508, 1991-10-25 (Released:2008-03-31)

参考文献数

24

被引用文献数

26 33

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Heptakis(6-O-(p-tosyl))-β-cyclodextrin and heptakis(6-O-(p-tosyl))-2-O-(p-tosyl)-β-cyclodextrin were prepared by the reaction of β-cyclodextrin with p-tosyl chloride in pyridine. They were converted to heptakis(3, 6-anhydro)-β-cyclodextrin, constituted from alternative (1C4) glucose units.

著者

大島 悦男 佐藤 秀幸 小場瀬 宏之 内村 達雄 桑原 隆 小林 智

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.40, no.9, pp.2552-2554, 1992-09-25 (Released:2008-03-31)

参考文献数

8

被引用文献数

2 6

---

(Z)-11-[3-(Dimethlamino)propylidene]-2-(methoxycarbonyl)methyl-6, 11-dihydrodibenz[b, e]oxepin-9-acrylic acid (5) was prepared for application to the radiommunoassay of KW-4679 (1, (Z)-11-[3-(dimethylamino)propylidene]-6, 11-dihydrodibenz[b, e]oxepin-2-acetic acid hydrochloride). The acrylic acid moiety in the 9-position of 5 was employed for coupling with an amino group of bovine serum albumin (BSA) to provide 17. Subsequently, the conjugate 17 was treated with aquenus NaOH to hydrolyze the terminal methoxycarbonyl group in the 2-position of the BSA conjugated 5. Antiserum raised against the antigenic BSA-conjugate 4 finally obtained was specific for 1.

著者

熊沢 利昭 大島 悦男 原川 洋行 佐藤 秀幸 小場瀬 宏之 生地 由昌 石井 昭男 石井 秀衛 大森 健守

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.39, no.10, pp.2729-2733, 1991-10-25 (Released:2008-03-31)

参考文献数

14

被引用文献数

2 4

---

New methods for the preparation of multi-functionallized-6, 11-dihydrodibenz[b, e]oxepins were developed. The structural requirements of KW-4994 (1), a promising orally active antiallergic agent, were defined. A carboxyl group at C-2 was critical for enhanced antiallergic of 1. The introduction of bromine atom at C-9 of 1 could elongate the duration of the action of the parent. Antiplatelet acetivity, a new pharmacological property of this series of compounds, was observed in one of the derivatives of 1.

著者

大島 悦男 熊沢 利昭 滝沢 博 原川 洋行 佐藤 秀幸 小場瀬 宏之 生地 由昌 石井 昭男 石井 秀衛 大森 健守

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.39, no.10, pp.2724-2728, 1991-10-25 (Released:2008-03-31)

参考文献数

28

被引用文献数

2 3

---

A new series of 11-substituted 6, 11-dihydrodibenz[b, e]oxepin derivatives was synthesized and evaluated for antiallergic activity. Convenient methods for the preparation of sulfides from alcohols were developed. Structure-activity relationships are described. Compound 7, 11-[2-(dimethylamino)ethyl]thio-6, 11-dihydrodibenz[b, e]oxepin-2-carboxylic acid hydrochloride, was the most potent in the rat passive cutaneous anaphylaxis test (ED50=0.92 mg/lg p.o.). It had a potent inhibitory effect on anaphylactic bronchoconstriction in guinea pigs (ED50=0.029 mg/kg p.o.) and H1 receptor antagonistic effect (Ki=14 nM) with few central nervous system side effects. Additionally, an antagonistic effect against prostagrandin D2-induced contraction of isolated guinea pig trachea (pA2=5.73) was an attractive mechanism of action of the new antiallergic agent. Compound 7 was selected for further evaluation as KW-4994.

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

川瀬 雅子 鮫島 啓二郎 岡田 正志 越智 清成 松永 功

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.33, no.6, pp.2395-2402, 1985-06-25 (Released:2008-03-31)

参考文献数

14

被引用文献数

2 5

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Derivatives of 5-fluorouracil (5-FU) substituted at the N-1 position were synthesized in order to investigate their enzymatic conversion to N1-(2-formylethyl)-5-FU, which is expected to give 5-FU with concomitant release of acrolein. Proton nuclear magnetic resonance spectroscopic studies of authentic N1-(2-formylethyl)-5-FU suggested that the compound exists in an equilibrium mixture of free aldehyde and cyclic hemiacetal forms. Spontaneous liberation of 5-FU from N1-(2-formylethyl)-5-FU at neutral pH was demonstrated by thin-layer chromatography using both the authentic compound and N1-(3-aminopropyl)-5-FU after treatment with amine oxidase, but the release of 5-FU seemed to be limited. Cytotoxicity was observed with N1-(2-formylethyl)-5-FU and N1-(3-aminopropyl)-5-FU, but none of the derivatives of 5-FU presently prepared showed a positive effect on P388 leukemia inoculated into mice.

著者

佐伯 清太郎 林 貴昭 浜名 政和

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.32, no.6, pp.2154-2159, 1984-06-25 (Released:2008-03-31)

参考文献数

2

被引用文献数

1 6

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The pseudo-Gomberg reaction of 1-substituted pyrrole derivatives with substituted anilines was examined. Pyrrole derivatives with electron-attracting groups at the 1-position, i.e., ethoxycarbonyl, methanesulfonyl, and benzoyl groups, were found to react smoothly with nitroaniline, chloroaniline and aniline. In each case, 2-arylated pyrrole derivatives were obtained in good or moderate yields.

著者

佐伯 清太郎 近藤 幸子 林 貴昭 浜名 政和

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.32, no.5, pp.1780-1789, 1984-05-25 (Released:2008-03-31)

参考文献数

6

被引用文献数

2 6

---

The 1-oxido-4-pyridyl radical generated by the reaction of 4-aminopyridine 1-oxide with amyl nitrite reacted smoothly with aromatic hydrocarbons, including five-membered heterocycles, i.e. thiophene, furan and pyrrole, to give the arylated products when acetic acid was used as the solvent. The relative rates of reaction with the 1-oxido-4-pyridyl radical indicated that this radical is electrophilic, and this finding was supported by a comparison of molecular orbital energy levels. 2-Aminopyridine 1-oxide also undergoes a similar reaction.

著者

Katsuhiro KONNO Katsuji OJIMA Takaaki HAYASHI Miyuki TANABE Hiroaki TAKAYAMA

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.45, no.1, pp.185-188, 1997-01-15 (Released:2008-03-31)

参考文献数

15

被引用文献数

4 6

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Synthesis of a 1α, 25-dihydroxyvitamin D2 analog (3), in which the double bond in the side-chain in replaced by an amide group, is described. Condensation of a carboxylic acid (8) with an amine (6) gave an amide (9), which in turn led to 3 via several steps. The analog (3) could not bind to the chick cytosol vitamin D receptor, which indicated the importance of the hydrophobic interaction of the C(22)-C(23) double bond in 1α, 25-dihydroxyvitamin D2 (2) with the vitamin D receptor.

著者

林 貴昭 尾島 克二 紺野 勝弘 間中 明彦 山口 健太郎 山田 幸子 高山 浩明

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.40, no.11, pp.2932-2936, 1992-11-25 (Released:2008-03-31)

参考文献数

16

被引用文献数

5 4

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A new synthesis of 24-fluoro-1α, 25-dihydroxyvitamin D2 (4a) and its 24-epimer (4b) is described. Starting with 1α, 3β-bis[(tert-butyldimethylsilyl)oxy]-24-norchol-5, 7-dien-23-al (5), a mixture of 4a and 4b was obtained in 3% overall yield in 6 steps. Reversed-phase HPLC cleanly separated the mixture into the two C-24 epimers. The X-ray crystallographic analysis of the 4-phenyl-1, 2, 4-triazoline-3, 5-dione (PTAD) adduct 11b, which was derived from the ester 6, unambiguously determined the configuration at C-24 of this compound. Based on the X-ray analysis, the configuration at C-24 of 4a and 4b was unequivocally determined.

著者

紺野 勝弘 尾島 克二 林 貴昭 高山 浩明

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.40, no.5, pp.1120-1124, 1992-05-25 (Released:2008-03-31)

参考文献数

17

被引用文献数

15 24

---

An alternative synthesis of the title compound 2, a highly potent analog of 1α, 25-dihydroxyvitamin D3 (1), is described. Starting with 1α, 3β-bis[(tert-butyldimethylsilyl)oxy]androst-5-ene (8), 2 was obtained in 3.8% total yield through 10 steps. This method provides compound 2 in much higher yield than that reported previously.

著者

Toshio Honda Hitoshi Wakabayashi Kazuo Kanai

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.50, no.2, pp.307-308, 2002 (Released:2002-06-30)

参考文献数

23

被引用文献数

33 42

---

Chiral β-amino esters are synthesized in one-pot from three components, amines, aldehydes, and ethyl bromoacetate, under the rhodium-catalyzed Reformatsky-type reaction condition, where complete diastereoselection is achieved in the nucleophilic addition step of ethyl bromoacetate to the imines prepared in situ.

著者

Koichiro Nishimura Toshikazu Saitoh

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.64, no.7, pp.1043-1046, 2016-07-01 (Released:2016-07-01)

参考文献数

3

被引用文献数

1 1

---

The 5-bromo-2-methylamino-8-methoxyquinazoline (1) is a key intermediate in our drug discoveries. Compound 1 bears a monomethylamino group at the 2-position of the quinazoline ring. This compound has been synthesized from 6-bromo-2-fluoro-3-methoxybenzaldehyde by a synthetic route including a total of four isolation processes in the medicinal chemistry laboratories. Our process chemistry laboratories successfully improved the original synthetic route by introducing the telescoping process. We successfully reduced the isolation processes from four to two processes by using information extracted through design of experiment. The total yield of compound 1 increased by 18%, while maintaining the purity of compound 1 of the original synthetic route. Accordingly, we contributed to the quick supply of compound 1 to the medicinal laboratories.

著者

廣橋 満 木戸 勝 山本 栄仁 小島 裕 實川 浩一郎 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.41, no.9, pp.1498-1506, 1993-09-15 (Released:2008-03-31)

参考文献数

23

被引用文献数

6 10

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The reactivities of 5-fluorouracil (5-FUra) degradation inhibitors, 2, 4- (2) and 2, 6-dihydroxypyridines (3), were investigated. Acylation of 2 and 2, 4-bis(trimethylsilyloxy)pyridines with equimolar amounts of acid chlorides preferentially occurred at the 4-OH and 2-OH positions, respectively, and the structure of monobenzoylated 5-chloro-2, 4-dihydroxypyridine (2b) was determined as 4-benzoyloxy-5-chloro-2-pyridone (5b) by X-ray crystallo-graphic analysis. Compounds 2 and 3, as well as the N-2-tetrahydrofuryl (11), N-alkyl (12), and N-carbamoyl (14) derivatives of 2, exhibit dynamic keto-enol tautomerism. The acyl derivatives of these pyridines are labile and are thought to be active esters. Monoacyl ester derivatives of these pyridines were combined with 5-FUra analogs to develop novel antitumor agents containing an inhibitor of 5-FUra degradation. One of them, 3-[3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)benzoyl]-1-ethoxymethyl-5-fluorouracil (BOF-A2) (22b), was the most effective and is currently undergoing late phase-II clinical trials.

著者

尾崎 庄一郎 渡辺 裕 星子 知範 水野 晴雄 石川 勝敏 森 春樹

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.32, no.2, pp.733-738, 1984-02-25 (Released:2008-03-31)

参考文献数

16

被引用文献数

20 24

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The toxicity and tumor affinity of 5-fluorouracil (1) have been modified by the introduction of acyloxyalkyl group (s) at the 1-, 3- or 1, 3-position (s) of 1. 1-Acyloxyalkyl-5-fluorouracil (3), 3-acyloxyalkyl-5-fluorouracil (4) and 1, 3-bis (acyloxyalkyl)-5-fluorouracil (5) were obtained by three methods : i) the reaction of α-chloroalkyl carboxylate (2) with 1, ii) the reaction of alkylidene diacylate with 2, 4-bis (trimethylsilyloxy)-5-fluoropyrimidine, iii) partial hydrolysis of 5. Compounds 3, 4 and 5 showed antitumor activity.

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

JUN-ICHI YAMASHITA SETSUO TAKEDA HIROSHI MATSUMOTO TADAFUMI TERADA NORIO UNEMI MITSUGI YASUMOTO

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.35, no.5, pp.2090-2094, 1987-05-25 (Released:2009-10-19)

参考文献数

14

被引用文献数

6 6

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Various O-acyl and N-acyl derivatives of 2'-deoxy-5-trifluoromethyluridine (F3Thd) were synthesized; namely 5'-O-acyl, 3', 5'-di-O-acyl, N3-acyl, 3', 5'-di-O-acetyl-N3-acyl, 3', 5'-di-O-carbamoyl and 3', 5'-di-O-ethoxycarbonyl compounds. 5'-O-Acyl derivatives of 2'-deoxy-5-trifluoromethylcytidine were also synthesized.The antitumor activities of these compounds against sarcoma 180 were examined by oral administration to mice. Among the 5'-and 3', 5'-diester compounds with aliphatic acids, the 5'-O-hexanoyl compound showed the highest activity. Full protection of the sugar moiety with aroyl or carbamoyl groups considerably decreased the activities, and those of the 3', 5'-di-O-m-fluorobenzoyl and 3, 5'-di-O-butylcarbamoyl compounds were the smallest. N3-Benzoyl compounds were slightly more effective than F3Thd but none of them showed higher activity than the effective O-acyl compounds. In the case of 5'-O-acylates of 2'-deoxy-5-trifluoromethylcytidine, the 5'-O-benzoyl compound showed the highest activity.

著者

Atsuhiko UEMURA Yukio TADA Setsuo TAKEDA Junji UCHIDA Jun-ichi YAMASHITA

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.44, no.1, pp.150-155, 1996-01-15 (Released:2008-03-31)

参考文献数

20

被引用文献数

3 3

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Various O-alkyl derivatives of 2'-deoxy-5-fluorouridine (FUdR) were synthesized and their antitumor activities in mice bearing sarcoma 180 (s.c.-p.o.) were evaluated in terms of the ED50 values (mg/kg/d). Most of these compounds were superior to FUdR in antitumor activity. In particular, the antitumor activity of 3'-O-(p-chloro-benzyl)-FUdR (3e) (ED50 =0.87mg/kg/d) was as much as 100 times that of FUdR (ED50=84mg/kg/d). Further, various 5'-O-aminoacyl derivatives of 3e were synthesized and evaluated in terms of ED50 value and therapeutic index (T.I.). Both the ED50 value (0.41mg/kg/d) and the T.I. (4.18) of 3'-O-(p-chlorobenzyl)-5'-O-glycyl-FUdR hydrochloride (6a) were significantly improved, compared with those of 3e and FUdR. FUdR plasma concentration after a single p.o. dosing of 6a was maintained for as long as 24h.

著者

尾崎 庄一郎 秋山 隆彦 池 祥雅 森 春樹 星 昭夫

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.37, no.12, pp.3405-3408, 1989-12-25 (Released:2008-03-31)

参考文献数

13

被引用文献数

14 15

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With the aim of diminishing the toxicity of 5-fluorouridine (1) and obtaining biologically active derivatives of 1, various kinds of 5'-O-acyl-8-fluorouridines 2 were synthesized. The antitumor activity of the compounds against L-1210 leukemia in mice was examined. The 5'-O-heptanoyl derivative 2h showed the highest antitumor activity.

著者

小林 義郎 熊懐 稜丸 大沢 昭緒 山田 猛

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.20, no.8, pp.1839, 1972-08-25 (Released:2008-03-31)

被引用文献数

15 20