著者

IKUO ADACHI TERUO YAMAMORI YOSHIHARU HIRAMATSU KATSUNORI SAKAI SHIN-ICHI MIHARA MASARU KAWAKAMI MASAO MASUI OSAMU UNO MOTOHIKO UEDA

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.36, no.11, pp.4389-4402, 1988-11-25 (Released:2011-02-08)

参考文献数

19

被引用文献数

31 49

---

A series of 4-aryl-4, 7-dihydrothieno [2, 3-b] pyridine-5-carboxylate derivatives (I) was synthesized and tested for binding affinity to Ca2+ channels in rat cerebral cortex membranes, coronary vasodilator effect in isolated guinea pig hearts, and antihypertensive activity in spontaneously hypertensive rats.Several compounds had potent coronary vasodilator and antihypertensive activities.The structure-ctivity relationships of the series indicated that a lipophilic 3-alkyl substituent with moderate bulkiness was effective for enhancing the pharmacological potencies.Among them, methyl 4, 7-dihydro-3-isobuty1-6-methy1-4-(3-nitrophenyl) thieno [2, 3-b] pyridine-5-carboxylate (S-312) was selected as a promising cardiovascular agent.The relationship between the absolute configuration of S-312 and its biological activities is also presented.

著者

加納 日出夫 足達 郁夫

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.16, no.1, pp.117-125, 1968-01-25 (Released:2008-03-31)

被引用文献数

6 12

---

Nine bicyclic isoxazolines (IVa-g and Va-b) were prepared by 1, 3-dipolar cycloaddition of nitrile oxides to the following heterocyclic olefins : 2, 3-and 2, 5-dihydrofurans, 5-methyl-2, 3-dihydrofuran, 2, 3-dihydropyran, and N-acetyl-2-piperidein. Acid-catalized cleavage of IVa-d gave the corresponding 4-substituted 3-phenylisoxazoles (VIa-c and IIIg). Nine 4-aminoalkyl-3-phenylisoxazoles (IIIa-i) were prepared for pharmacological testings in comparison with those of 3- and 5-aminoalkyl analogs (I and II). Base-catalized cleavage of the adducts (IVa-c and Va) was also investigated and in some cases the lactones (XIIa and XIIb) were obtained besides the isoxazoles (VIa and VIb). In this connection the Hofmann reactions of the bicyclic isoxazoline-3-carbon-amides (IVe'and IVf') were studied.

著者

足達 郁夫 加納 日出夫

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.17, no.11, pp.2201-2208, 1969-11-25 (Released:2008-03-31)

被引用文献数

5 12

---

Ring opening reactions with some bases were examined in the following quaternary salts : 2-ethyl-3, 4-diphenylisoxazolium chloroferrate (V), and 2, 4-dimethyl-3-phenyl-, 3, 4-diphenyl-2-methyl- and 2-methyl-3-phenylisoxazolium perchlorate (IXa, b and c). Treatments of V and IX with sodium alcoholate in alcohol gave the corresponding alkyl cinnamates (VIIa-e). By the use of aqueous sodium hydroxide, V and IXb gave the respective cinnamic anhydrides (Xa and b) contrary to the report of Kohler, et al., and IXa gave an unexpected product, 2, 5-diphenyl-1, 3, 4-trimethylpyrrole (XIa) along with usual ring cleaved products, XIIa and XIIIa. Reactions of IXa, b with several amines gave β-keto acid amides (XIIc-h), the ketones (XIIIa, b) and the pyrrole (XIa) (only from IXa), respectively. Reactions of IXa with Grignard reagents gave 5-substituted △3-isoxazolines (XIVa, b). Similar 5-amino-△3-isoxazolines (XVa-c) were obtained by cautious treatment of IXa, b with piperidine or morpholine. Solvolysis of X, XIV and XV were also investigated, and a tentative mechanism for the formation of the various products are presented.

著者

足達 郁夫 宮崎 理慧 加納 日出夫

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.22, no.1, pp.70-77, 1974-01-25 (Released:2008-03-31)

被引用文献数

16 29

---

Synthesis and thermal-reaction of 4-isoxazolines were investigated. Reaction of 3-unsubstituted isoxazolium salts with sodium borohydride yielded the corresponding 4-isoxazolines and their borane complexes together with β-hydroxyaminopropiophenone derivatives. Analogous reaction of 5-unsubstituted isoxazolium salt yielded two isomeric products, 4- and 3-isoxazoline derivatives. The 3-isoxazoline derivative underwent further reduction to give isoxazolidine derivatives. Thermal-conversion of some 4-isoxazolines and their borane complexes into 2-acylaziridine derivatives is also reported.

著者

足達 郁夫 山守 照雄 平松 義春 酒井 克則 三原 伸一 川上 勝 升井 正生 宇野 攻 上田 元彦

出版者

公益社団法人日本薬学会

雑誌

Chem Pharm Bull (Tokyo) (ISSN:00092363)

巻号頁・発行日

vol.36, pp.4389-4402, 1988

被引用文献数

1

---

A series of 4-aryl-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate derivatives (I) was synthesized and tested for binding affinity to Ca^<2+> channels in rat cerebral cortex membranes, coronary vasodilator effect in isolated guinea pig hearts, and antihypertensive activity in spontaneously hypertensive rats. Several compounds had potent coronary vasodilator and antihyper tensive activities. The structure-activity relationships of the series indicated that a lipophilic 3-alkyl substituent with moderate bulkiness was effective for enhancing the pharmacological potencies. Among them, methyl 4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno[2,3-b]-pyridine-5-carboxylate (S-312) was selected as a promising cardiovascular agent. The relationship between the absolute configuration of S-312 and its biological activities is also presented.

著者

Kazutaka Tachibana Ikuhiro Imaoka Takuya Shiraishi Hitoshi Yoshino Mitsuaki Nakamura Masateru Ohta Hiromitsu Kawata Kenji Taniguchi Nobuyuki Ishikura Toshiaki Tsunenari Hidemi Saito Masahiro Nagamuta Toshito Nakagawa Kenji Takanashi Etsuro Onuma Haruhiko Sato

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.57, no.10, pp.1178, 2009-10-01 (Released:2009-10-03)

著者

Takuya Shiraishi Shojiro Kadono Masayuki Haramura Hirofumi Kodama Yoshiyuki Ono Hitoshi Iikura Tohru Esaki Takaki Koga Kunihiro Hattori Yoshiaki Watanabe Akihisa Sakamoto Kazutaka Yoshihashi Takehisa Kitazawa Keiko Esaki Masateru Ohta Haruhiko Sato Toshiro Kozono

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.58, no.1, pp.38-44, 2010-01-01 (Released:2010-01-01)

参考文献数

29

被引用文献数

1

---

Selective factor VIIa-tissue factor complex (FVIIa/TF) inhibition is regarded as a promising target for developing new anticoagulant drugs. In previous reports, we described a S3 subsite found in the X-ray crystal structure of compound 2 that bound to FVIIa/soluble tissue factor (sTF). Based on the X-ray crystal structure information and with the aim of improving the inhibition activity for FVIIa/TF and selectivity against other serine proteases, we synthesized derivatives by introducing substituents at position 5 of the indole ring of compound 2. Among them, compound 16 showed high selectivity against other serine proteases. Contrary to our expectations, compound 16 did not occupy the S3-subsite; X-ray structure analysis revealed that compound 16 improved selectivity by forming hydrogen bonds with Gln217, Thr99 and Asn100.

著者

Kazutaka Tachibana Ikuhiro Imaoka Takuya Shiraishi Hitoshi Yoshino Mitsuaki Nakamura Masateru Ohta Hiromitsu Kawata Kenji Taniguchi Nobuyuki Ishikura Toshiaki Tsunenari Hidemi Saito Masahiro Nagamuta Toshito Nakagawa Kenji Takanashi Etsuro Onuma Haruhiko Sato

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.56, no.11, pp.1555-1561, 2008-11-01 (Released:2008-11-01)

参考文献数

21

被引用文献数

14 20

---

The 3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethylthiohydantoin derivatives which have carboxy-terminal side chains were synthesized and their agonistic/antagonistic activities against androgen receptor (AR) measured. Among them, compound 13b showed antagonistic activity (IC50=130 nM) with no agonistic activity even at 10000 nM. This compound exhibited significant metabolic stability and oral antiandrogenic activity (ED50=7 mg/kg).

著者

樫原 宏 篠木 浩 末宗 洋 酒井 浄

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.11, pp.4527-4532, 1986-11-25 (Released:2008-03-31)

参考文献数

16

被引用文献数

6 11

---

During the course of synthetic studies on the 5, 6-disubsituted 4-oxo-tetrahydro-2-pyroneskeleton in connection with biologically active compounds, we have found a convenient procedure for the regioselective introduction of a double bond in methyl alkyl ketones and a novel synthetic method for indan derivatives.

著者

藤井 郁雄 阿部 昌之 早川 謙二 兼松 顕

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.11, pp.4670-4673, 1984-11-25 (Released:2008-03-31)

参考文献数

5

被引用文献数

2 4

---

3, 4-Dimethoxy trans-6-morphinanone (1) and its cis isomer (2) were prepared stereoselectively from thebaine (3) and dihydrocodeinone (9), respectively. A general way of spectrally differentiating between these two stereoisomers is discussed.

著者

本田 昌徳 上田 義隆 杉山 重夫 古森 徹哉

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.6, pp.1385-1391, 1991-06-25 (Released:2008-03-31)

参考文献数

24

被引用文献数

12 20

---

A cerebroside, 1-O-(β-D-galactopyranosyloxy)-(2S, 3S, 4R, 6E)-2-[(R)-2-hydroxytetracosanoylamino]-17-methyl-6-octadecene-3, 4-diol (2), was asymmetrically synthesized from isobutyraldehyde. On the basis of a comparison of the physical data, the absolute structure of a new cerebroside 1b from a Chondropsis sp. sponge is thought to be the same at that of 2.

著者

宮内 正雄 笹原 邦宏 藤本 光一 川本 勲 井手 純也 中尾 英雄

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.9, pp.2369-2374, 1989-09-25 (Released:2008-03-31)

参考文献数

21

被引用文献数

10 9

---

The degradation kinetics of pivaloyloxymethyl (POM) esters of cephalosporins in phosphate buffer solution (pH6-8) were investigated. The degradation of the starting Δ3 cephalosporin ester proceeded mainly via isomerization to the Δ2 ester and subsequent hydrolysis to the Δ2 acid. Hydrolysis to the Δ3 acid (the parent acid) was very slow. Analysis of the rate constants indicated that the isomerization rate k12 was approximately equal to the apparent degradation rate of the Δ3 ester kdeg, and slower than the hydrolysis rate of the Δ2 ester k24. The isomerization process to the Δ2 ester was found to be the rate-determining step in the degradation of cephalosporin esters. The substituent at the C-3 position of the cephalosporins affected the degradation kinetics. The degradation was accelerated by increase of pH, buffer concentartion and added protein.

著者

宮内 正雄 笹原 邦宏 藤本 光一 川本 勲 井手 純也 中尾 英雄

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.37, no.9, pp.2369-2374, 1989

被引用文献数

9

---

The degradation kinetics of pivaloyloxymethyl (POM) esters of cephalosporins in phosphate buffer solution (pH6-8) were investigated. The degradation of the starting &Delta;<SUP>3</SUP> cephalosporin ester proceeded mainly via isomerization to the &Delta;<SUP>2</SUP> ester and subsequent hydrolysis to the &Delta;<SUP>2</SUP> acid. Hydrolysis to the &Delta;<SUP>3</SUP> acid (the parent acid) was very slow. Analysis of the rate constants indicated that the isomerization rate k<SUB>12</SUB> was approximately equal to the apparent degradation rate of the &Delta;<SUP>3</SUP> ester k<SUB>deg</SUB>, and slower than the hydrolysis rate of the &Delta;<SUP>2</SUP> ester k<SUB>24</SUB>. The isomerization process to the &Delta;<SUP>2</SUP> ester was found to be the rate-determining step in the degradation of cephalosporin esters. The substituent at the C-3 position of the cephalosporins affected the degradation kinetics. The degradation was accelerated by increase of pH, buffer concentartion and added protein.

著者

宮内 正雄 栗原 英志 藤本 光一 川本 勲 井手 純也 中尾 英雄

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.9, pp.2375-2378, 1989-09-25 (Released:2008-03-31)

参考文献数

17

被引用文献数

1 2

---

The effect of substituents at the C-3 position on the degradation kinetics of the pivaloyloxymethyl (POM) ester of Δ3 cephalosporin in phosphate buffer solution (pH6-8) was investigated. In the degradation, the isomerization process to the Δ2 ester was the rate-determining step. In this study, the logarithm of the isomerization rate to the Δ2 ester (log k12) correlated with the carbon-13 unclear magnetic resonance chemical shift difference value at C-3 and C-4 of the Δ3 ester (Δδ(4-3)). The energy level of the lowest unoccupied molecular orbital (LUMO) of the Δ3 esters also correlated with log k12. The electronic properties at the C-2 position had no effect on the isomerization reaction. On the other hand, the logarithm of the isomerization rate back to the Δ3 ester (log k21) correlated with the van der Waals volume (MV) of the 3-substituent. These results show that the substituent at the C-3 position influences mainly the electronic structure of the conjugated π-bond system (C3=C4-C4=O) and consequently affects the feasibility of isomerization to the Δ2 ester, i.e., the stability to degradation.

著者

宮内 正雄 栗原 英志 藤本 光一 川本 勲 井手 純也 中尾 英雄

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.37, no.9, pp.2375-2378, 1989

被引用文献数

2

---

The effect of substituents at the C-3 position on the degradation kinetics of the pivaloyloxymethyl (POM) ester of &Delta;<SUP>3</SUP> cephalosporin in phosphate buffer solution (pH6-8) was investigated. In the degradation, the isomerization process to the &Delta;<SUP>2</SUP> ester was the rate-determining step. In this study, the logarithm of the isomerization rate to the &Delta;<SUP>2</SUP> ester (log k<SUB>12</SUB>) correlated with the carbon-13 unclear magnetic resonance chemical shift difference value at C-3 and C-4 of the &Delta;<SUP>3</SUP> ester (&Delta;&delta;(4-3)). The energy level of the lowest unoccupied molecular orbital (LUMO) of the &Delta;<SUP>3</SUP> esters also correlated with log k<SUB>12</SUB>. The electronic properties at the C-2 position had no effect on the isomerization reaction. On the other hand, the logarithm of the isomerization rate back to the &Delta;<SUP>3</SUP> ester (log k<SUB>21</SUB>) correlated with the van der Waals volume (MV) of the 3-substituent. These results show that the substituent at the C-3 position influences mainly the electronic structure of the conjugated &pi;-bond system (C<SUB>3</SUB>=C<SUB>4</SUB>-C<SUB>4</SUB>=O) and consequently affects the feasibility of isomerization to the &Delta;<SUP>2</SUP> ester, i.e., the stability to degradation.

著者

中尾 英雄 荒川 順生 中村 隆洋 福島 正美

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.9, pp.1968-1979, 1972-09-25 (Released:2008-03-31)

被引用文献数

24 31

---

A series of 2, 5-bis (1-aziridinyl)-p-benzoquinone derivatives were synthesized and evaluated as antileukemic agents. The most active compounds against lymphoid leukemia L-1210 in BDF1 mice were 2, 5-bis (1-aziridinyl)-3-(2-carbamoyloxyethyl-1-methoxy)-6-methyl-p-benzoquinone, carbazilquinone (7), and related compounds (8, 23 and 24). Structure-activity relationships were discussed.

著者

中尾 英雄 荒川 順生

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.9, pp.1962-1967, 1972-09-25 (Released:2008-03-31)

被引用文献数

8 13

---

A series of p-benzoquinone derivatives having one or two carbamoyloxyalkyl groups in the 2 and/or 5-positions were synthesized and evaluated as antileukemic agents. Among these compounds 2, 5-bis (1-aziridinyl)-3-(2-carbamoyloxyethyl)-6-methyl-p-benzoquinone (21) showed high activity against lymphoid leukemia L-1210 in BDF1 mice.

著者

斉藤 仁 好川 博 西村 吉雄 近藤 信一 竹内 富雄 梅澤 濱夫

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.9, pp.3741-3746, 1986-09-25 (Released:2008-03-31)

参考文献数

11

被引用文献数

17 25

---

D-(and L-)2, 6-Dideoxy-2-aminoglycosidic variants of 4'-O-demethyl-1-epipodophyllotoxin were synthesized by glycosidation of 4'-O-benzyloxycarbonyl- or 4'-O-chloroacetyl-4'-O-demethyl-1-epipodophyllotoxin (6 or 14) with the corresponding aminosugar derivatives. 1-O-(2-Amino-2-deoxy-4 : 6-O-ethylidene-β-D-glucopyranosyl)-4'-O-demethyl-1-epipodophyllotoxin (18) reacted with aldehydes in the presence of sodium cyanoborohydride, or reacted with α, β-unsaturated esters, or with α, β-unsaturated nitriles to yield the corresponding N-alkyl analogs. A number of the 4'-O-demethyl-1-epipodopyllotoxin β-D-aminoglycoside derivatives gave significant survival time increases in mice with leukemia L-1210. In particular, 1-O-(2-dimethylamino-2-deoxy-4 : 6-O-ethylidene-β-D-glucopyranosyl)-4'-O-demethyl-1-epipodophyllotoxin (19) showed superior activity to VP-16-213 (etoposide, 1).

著者

堀 耕造 野村 敬一 数野 秀樹 吉井 英一

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.38, no.6, pp.1778-1780, 1990-06-25 (Released:2008-03-31)

参考文献数

15

被引用文献数

3 4

---

L-Rhamnal has been transformed into the tetrahydrofuran subunits (14 and 21) of tetronasin (ICI-139603) (1) and tetronomycin (2), in which the three chiral centers at the 2- and 5-positions and the methoxy-bearing carbon are of mirror image.

著者

渡辺 淳 岡部 博 溝尻 顕爾 中島 善次 菅野 浩一 山本 隆一

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.27, no.5, pp.1075-1084, 1979-05-25 (Released:2008-03-31)

被引用文献数

1

---

The drug was well absorbed from the intestinal tract, and the bulk of it was excreted in the urine and feces. Biliary excretion was significant, and the existence of enterohepatic circulation was considered likely. After intravenous injection, elimination of radioactivity from the blood and various tissues, except for fat, was rapid for 2 hr, then became slower. Elimination of unchanged drug from the blood was very fast. Repeated oral doses did not changed the excretion and distribution features as compared to a single oral dose. Significant accumulation of radioactivity was not caused by repeated doses of 14C-labeled perisoxal. Three oxidized metabolites, p-hydroxyperisoxal, m-hydroxyperisoxal and 4-hydroxyperisoxal, were identified. Excretion of hydroxyperisoxals in the urine (free and conjugates) was greater than that of perisoxal itself.