- 著者
- 沢田 誠吾 八重樫 隆 古田 富雄 横倉 輝男 宮坂 貞
- 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.41, no.2, pp.310-313, 1993-02-15
7-Ethylcamptothecin (1d), a model which does not have any site on the A-ring for further modification was converted into water-soluble derivatives by opening the E-ring lactone. 1d was heated in N, N-dimethylenediamine to yield amide 2a, and this was then acylated to furnish 3a-q, which were soluble in water as their HCl salts. The propionyl (3b), butyryl (3c) and methylthiopropionyl (3h) derivatives showed higher activity than the sodium salt of 1d. The acyl group makes the derivatives more lipophilic, and ease of hydrolysis of amide 2a to 1d is thought to be necessary for significant activity.
- 著者
- Matsuda Akira Takenuki Kenji Itoh Hiroko Sasaki Takuma Ueda Tohru
- 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.35, no.9, pp.3967-3970, 1987
- 被引用文献数
- 32
We have synthesized 2'-deoxy-2' (S) -methylcytidine (7), a new antileukemic nucleoside. The carbonyl methylation of 2'-ketonucleoside (1) with MeLi, Me<SUB>3</SUB>Al and MeMgX was examined. Only in the reaction with MeMgX, did the more hindered β-attack afford the 2'-methyl-t-alcohol (2b). Compound 2b was converted into the methyl oxalate (4), which was subjected to radical deoxygenation to give the 2'-deoxy-2' (S) -methyl derivative (5). The deprotection of 5 followed by substitution with NH<SUB>3</SUB> furnished 7. The structure-activity relationships of 7 and some other 2'-branched-chain sugar cytidines against L1210 cells are also described.
- 著者
- 松田 彰 南川 典昭 佐々木 琢磨 上田 亨
- 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.36, no.7, pp.2730-2733, 1988
- 被引用文献数
- 32
The design, synthesis and antileukemic activity of 5-alkynel-1-β-D-ribofuranosylimidazole-4-carboxamides (6) are described. The cross-coupling reaction of 5-iodo-1-(2, 3, 5-tri-O-acetyl-β-D-ribofuranosyl)imidazole-4-carboxamide (8) with various terminal alkynes in the persence of bis(benzonitrile)palladium dichloride and triethylamine in acetonitrile gave 5-alkylnyl derivatives (9) in high yields. Coupling of 8 with (trimethylsilyl)acetylene gave hte undesired dimer (10). Instead of (trimethylsilyl)acetylene, treatment of trimethyl[(tributyl-satannyl)ethynyl]silane with 8 in the absence of triethylamine produced the desired 5-[2-(trimethylsilyl)ethynyl] derivative (9f) in 77% yield. Deblocking of these nucleosides (9) gave the target nucleosides (6a-f). Among them, 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxyamide (6f) is the most potent inhibitor of the growth of murine L1210 cells in vitro (IC<SUB>50</SUB>=0.18 μg/ml).
- 著者
- 松田 彰 伊藤 弘子 竹貫 健二 佐々木 琢磨 上田 亨
- 出版者
- 公益社団法人日本薬学会
- 雑誌
- Chem. Pharm. Bull. (ISSN:00092363)
- 巻号頁・発行日
- vol.36, pp.945-953, 1988
- 被引用文献数
- 1
The reaction of 4-ethoxy-1-(3,5-O-tetraisopropyldisiloxanyl-1,3-diyl-β-D-erythro-pentofuran-2-ulosyl)-2(1H)-pyrimidinone (11) with various organometallic reagents yielded corresponding 2'-branched-chain sugar pyrimidine nucleosides. Only in the reactions with MeMgBr and EtMgBr was the more hindered β-attack observed to afford and 2'-alkyl ribofuranosides (13a, b). In the reaction of 11 with MeLi, Me_3,Al, or PhMgBr, 2'-methyl or phenyl arabinosides (12a, b, c)were obtained stereoselectively. Conversion of these pyrimidine nucleosides into cytosine derivatives is also described and their antileukemic and antiviral activities are discussed.
- 著者
- 松田 彰 南川 典昭 佐々木 琢磨 上田 亨
- 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.36, no.7, pp.2730-2733, 1988-07-25
The design, synthesis and antileukemic activity of 5-alkynel-1-β-D-ribofuranosylimidazole-4-carboxamides (6) are described. The cross-coupling reaction of 5-iodo-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)imidazole-4-carboxamide (8) with various terminal alkynes in the persence of bis(benzonitrile)palladium dichloride and triethylamine in acetonitrile gave 5-alkylnyl derivatives (9) in high yields. Coupling of 8 with (trimethylsilyl)acetylene gave hte undesired dimer (10). Instead of (trimethylsilyl)acetylene, treatment of trimethyl[(tributyl-satannyl)ethynyl]silane with 8 in the absence of triethylamine produced the desired 5-[2-(trimethylsilyl)ethynyl] derivative (9f) in 77% yield. Deblocking of these nucleosides (9) gave the target nucleosides (6a-f). Among them, 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxyamide (6f) is the most potent inhibitor of the growth of murine L1210 cells in vitro (IC_<50>=0.18 μg/ml).
- 著者
- 江島 明男 寺沢 弘文 杉森 正道 大薄 悟 松本 建介 川戸 康義 安岡 周美 田川 博昭
- 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.40, no.3, pp.683-688, 1992
- 被引用文献数
- 21
Several E-ring-modified analogues of (RS)-camptothecin were synthesized by total synthesis via Friedlander condensation and evaluated for cytotoxicity and antitumor activity against P388 mouse leukemia cells. Among them, (RS)-20-deoxyamino-7-ethyl-10-methoxycamptothecin (25c) was found to be more active than (RS)-camptothecin (1) in the in vivo assay.
- 著者
- 沢田 誠吾 野方 健一郎 古田 富雄 横倉 輝男 宮坂 貞
- 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.39, no.10, pp.2574-2580, 1991
- 被引用文献数
- 56
A radical substitution reaction of 20(S)-camptothecin (1) with methanol furnished 7-hydroxymethylcamptothecin (2). Reaction of 1 with primary alcohols higher than methanol gave 7-alkylcamptothecins (4), of which alkyl groups were one carbon less than the alcohols used and also 7-hydroxyalkylcamptothecins (5). For the preparation of 7-alkylcamptothecin (4), aldehydes were used as a radical source and several alkylated derivatives were synthesized. 7-Acyloxymethyl derivatives (6), 7-carbaldehyde (7), iminomethyl derivatives (10), acid (11), esters (12) and amides (13) were synthesized starting from 2. 7-Ethyl-(4b) and 7-propylcamptothecin (4c), acyloxymethyl compounds 6a, 6c and ethyl ester (12b) exhibited higher antitumor activity than 1 against L1210 in mice.
- 著者
- 沢田 誠吾 松岡 俊一 野方 健一郎 永田 洋 古田 富雄 横倉 輝男 宮坂 貞
- 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.39, no.12, pp.3183-3188, 1991
- 被引用文献数
- 57
20(S)-Camptothecin derivatives having nitro, amino, chloro, bromo, hydroxyl and methoxyl groups in the A-ring were synthesized. B-Ring hydrogenated camptothecin (2a) was converted into 10-hydroxycamptothecin (6e) by treatment with lead tetraacetate in trifluoroacetic acid. 10-Substituted derivatives (6) were obtained by a photoreaction of N-oxides (9). The cytotoxicity o the A-ring modified camptothecins was evaluated against KB cells in vitro and leukemia L1210 in mice. 7-Ethyl-10-hydroxycamptothecin (6i) was identified as a potential derivative for further modification.
- 著者
- 沢田 誠吾 岡島 悟 相山 律男 野方 健一郎 古田 富雄 横倉 輝雄 杉野 栄一 山口 健太郎 宮坂 貞
- 出版者
- 公益社団法人日本薬学会
- 雑誌
- Chem. Pharm. Bull. (ISSN:00092363)
- 巻号頁・発行日
- vol.39, pp.1446-1454, 1991
- 被引用文献数
- 9
Nevel 36 derivatives (6), bonding the phenolic hydroxyl group of 7-ethyl-10-hydroxycamptothecin (4) with diamines through a monocarbamate linkage, were synthesized and their antitumor activity was evaluated in vivo. The derivatives were soluble in water as their HC1 salts wiht the E lactone ring intact and exhibited significant antitumor activity. One of the derivatives, 6-27 showed excellent activity against L1210 leukemia and other murine tumors.The structure of its hydrochloride trihydrate (CPT-11) was determined by spectroscopic and crystallographic methods.
- 著者
- 八重樫 隆 沢田 誠吾 永田 洋 古田 富雄 横倉 輝男 宮坂 貞
- 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.42, no.12, pp.2518-2525, 1994
- 被引用文献数
- 42
Twenty-six novel A-ring-modified 7-ethylcamptothecins (6) were synthesized by Friedlander's condensation of the chiral tricyclic ketone (5) with aminopropiophenones (4). The compounds substituted with fluorine at the 11 position showed strong cytotoxicity to KB and L1210 cells. The 11-fluoro derivatives also exhibited strong inhibitory activity on DNA topoisomerase I. Nine compounds 6 with four to ten times stronger cytotoxicity than that of camptothecin were selected and converted into water-soluble 17-O-acyl amide derivatives (8). Compounds 8e (10-Me, O-COCH<SUB>2</SUB>CH<SUB>2</SUB>SCH<SUB>3</SUB>) and 8f (11-F, O-COC<SUB>2</SUB>H<SUB>5</SUB>) showed activity towards Meth A in mice that was comparable to that of CPT-11, at lower doses than CPT-11.
- 著者
- 八重樫 隆 沢田 誠吾 永田 洋 古田 富雄 横倉 輝男 宮坂 貞
- 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.42, no.12, pp.2518-2525, 1994-12-15
Twenty-six novel A-ring-modified 7-ethylcamptothecins (6) were synthesized by Friedlander's condensation of the chiral tricyclic ketone (5) with aminopropiophenones (4). The compounds substituted with fluorine at the 11 position showed strong cytotoxicity to KB and L1210 cells. The 11-fluoro derivatives also exhibited strong inhibitory activity on DNA topoisomerase I. Nine compounds 6 with four to ten times stronger cytotoxicity than that of camptothecin were selected and converted into water-soluble 17-O-acyl amide derivatives (8). Compounds 8e (10-Me, O-COCH_2CH_2SCH_3) and 8f (11-F, O-COC_2H_5) showed activity towards Meth A in mice that was comparable to that of CPT-11,at lower doses than CPT-11.
- 著者
- 田中 博道 高橋 隆子 富樫 浩之 上田 亨
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Chemical and Pharmaceutical Bulletin (ISSN:00092363)
- 巻号頁・発行日
- vol.26, no.11, pp.3322-3329, 1978-11-25 (Released:2008-03-31)
- 被引用文献数
- 5 8
Starting from 1-β-D-ribofuranosyl-2-oxo-4-imidazoline-4-carboxylic acid (1), obtained from uridine, various 2, 5'-O-cycloimidazole nucleosides have been prepared. The 2-oxo function of 1 was also converted to the 2-chloro and 2-thione functions. Whereas the circular dichroism (CD) spectra of 1 and related 2-oxo derivatives exhibited negative bands, their 5-bromo derivatives showed positive bands. All 2, 5'-O-cycloimidazole nucleosides showed strong negative CD bands which were in contrast to the results in the 8, 5'-O-cyclopurine nucleosides. The relationship between the sign of the CD bands and the orientation of the base moieties in imidazole nucleosides was discussed.
- 著者
- 末宗 洋 小田 晃造 佐伯 清太郎 酒井 浄
- 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.36, no.1, pp.172-177, 1988-01-25
This paper describes the conversions of (-)-limonene to four nepetalactones (1,2,ent-3 and 4) in a stereocontrolled manner. The cis-3,4-disubstituted cyclopentanone (5) obtained from (-)-limonene via Rh(I)-catalyzed cyclization of the 4-pentenal, could be converted to the bicyclo[3.3.0]octenone (6). After the stereoselective conversion of 6 into the diastereomeric isomers of the ketones (8 and 16), a sequence of reactions involving the silyl enol ethers (18 and 19), ozonolysis, and subsequent lactonization afforded the target molecules.
- 著者
- 末宗 洋 丸岡 博 佐伯 清太郎 酒井 浄
- 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.34, no.11, pp.4629-4634, 1986-11-25
This paper describes a conversion of (-)-limonen-10-ol to the key intermediate (1) for 11-deoxyprostaglandin. The 3,4-cis-disubstituted cyclopentanone (2), which was easily obtained from (-)-limonen-10-ol in a stereocontrolled fashion by means of Rh(I)-catalyzed cyclization via the 4-pentenal derivative, could be directly converted to the bicyclo[3.3.0]octenone (3) by treatment with KHSO_4 in boiling benzene. Compound 3 with a double bond at the favorable position was converted to 1 by way of fission of the double bond and subsequent modification of substituents on the five-membered ring.
- 著者
- 末宗 洋 原部 哲治 謝 卓峰 酒井 浄
- 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.36, no.11, pp.4337-4344, 1988-11-25
Asymmetric hydrolysis of 2,2-bis(acetoxymethyl)cyclopentanone (5) using biocatalysis and its application to a formal synthesis of (-)-melyngolide are described. For the asymmetric induction at the quanternary carbon of 5,cholinesterase from electric eel was found to be effective to afford the (+)-monoacetate (6) (90%ee). Compound (+)-6 was easily converted to the synthetic intermediate (28) for (-)-malyngolide.
- 著者
- 末宗 洋 原部 哲治 酒井 浄
- 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.36, no.9, pp.3632-3637, 1988-09-25
Two trihydroxy unsaturated C-18 fatty acids [(9S, 12S, 13S)-trihydroxyoctadeca-10E, 15Z-dienoic acid (methyl ester) and (9S, 12S, 13S)-trihydroxy-10E-octadecenoic acid (methyl ester)] isolated from rice plants as agents with activity against blast disease were synthesized from (+)-dimethyl tartrate.
- 著者
- 宮澤 修平 岡野 和夫 下村 直之 川原 哲也 浅野 修 吉村 寛幸 河合 隆利 左右田 茂 吉田 豊 里 忠 町田 善正 山津 功
- 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.2, pp.521-523, 1992-02-25 (Released:2008-03-31)
- 参考文献数
- 14
- 被引用文献数
- 2 4
Optically active platelet-activating factor (PAF) receptor antagonist, (+)-6-(2-chlorophenyl)-3-cyclopropanecarbonyl-8, 11-dimethyl-2, 3, 4, 5-tetrahydro-8H-pyrido[4', 3' : 4, 5]thieno[3, 2-f][1, 2, 4]triazolo[4, 5-a][1, 4]diazepine (E6123), was synthesized on large-scale by optical resolution using (+)-dibenzoyl-D-tartaric acid. An X-ray crystallographic analysis clearly indicated that the absolute configuration of the synthesized E6123 was S.
- 著者
- 宮澤 修平 岡野 和夫 下村 直之 / 川原 哲也 浅野 修 吉村 寛幸 宮本 光明 佐久間 義範 村本 賢三 尾葉石 浩 原田 耕吉 梶間 隆 山田 浩司 角田 創 片山 敏 阿部 信也 浅川 直樹 左右田 茂 堀江 透 里 忠 町田 善正 片山 幸一 山津 功 Isao YAMATSU
- 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.12, pp.3215-3220, 1991-12-25 (Released:2008-03-31)
- 参考文献数
- 27
- 被引用文献数
- 6 9
A series of triazolodiazepines was synthesized and evaluated for anti-platelet activating factor (PAF) activities. Structure-activity relationship (SAR) studies on this series revealed that the introduction of a methyl group into the 8-position of the thienodiazepine nucleus can lead to a lengthening of the duration of action. Introduction of a methyl group produced an asymmetric center and the enantiomers so formed were separated with an optical resolving column. In the in vitro assay system, the (+)-isomers displayed 50-200 times more potent anti-PAF activity than the (-)-isomers. After comparison of toxicology and pharmacokinetics, (+)-6-(2-chlorophenyl)-3-cyclopropanecarbonyl-8, 11-dimethyl-2, 3, 4, 5-tetrahydro-8H-pyrido[4', 3' : 4, 5]thieno[3, 2-f][1, 2, 4]triazolo[4, 3-a][1, 4]diazepine (35(+)-isomer, E6123) was selected from among the compounds synthesized as a candidate for clinical study.
- 著者
- 末宗 洋 川原 哲也 酒井 浄
- 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.34, no.2, pp.550-557, 1986-02-25
Prostanoic acid (18) and 8-isoprostanoic acid (1) constitute the basic structures of primary prostaglandins and 8-isoprostaglandins. The conversion of commercially available (+)- and (-)-limonene to these compounds was accomplilshed by a sequence of reactions involving the Rh(I)-catalyzed cyclization of 3,4-disubstituted 4-pentenals, which were easily prepared from (+)- or (-)-limonene, to cis-3,4-disubstituted cyclopentanones and the appropriate modification of substituents on the five-membered ring.
- 著者
- Mio Tange Akino Matsumoto Miyako Yoshida Honami Kojima Tamami Haraguchi Takahiro Uchida
- 出版者
- 公益社団法人日本薬学会
- 雑誌
- Chemical and Pharmaceutical Bulletin (ISSN:00092363)
- 巻号頁・発行日
- vol.65, no.1, pp.36-41, 2017-01-01 (Released:2017-01-01)
- 参考文献数
- 28
- 被引用文献数
- 2
The purpose of the study was to evaluate the adsorption of filgrastim on infusion sets (comprising infusion bag, line and filter) and to compare the adsorption of the original filgrastim preparation with biosimilar preparations using HPLC. The inhibitory effect of polysorbate 80 on this adsorption was also evaluated. Filgrastim was mixed with isotonic sodium chloride solution or 5% (w/v) glucose solution in the infusion fluid. Filgrastim adsorption on infusion sets was observed with all preparations and with both types of infusion solution. The adsorption ratio was about 30% in all circumstances. Filgrastim adsorption on all parts of the infusion set (bag, line and filter) was dramatically decreased by the addition of polysorbate 80 solution at concentrations at or over its critical micelle concentration (CMC). The filgrastim adsorption ratio was highest at a solution pH of 5.65, which is the isoelectric point (pI) of filgrastim. This study showed that the degree of filgrastim adsorption on infusion sets is similar for original and biosimilar preparations, but that the addition of polysorbate 80 to the infusion solution at concentrations at or above its CMC is effective in preventing filgrastim adsorption. The addition of a total-vitamin preparation with a polysorbate 80 concentration over its CMC may be an effective way of preventing filgrastim adsorption on infusion sets.