HETEROCYCLES

■ Contents

■ Discovery of New Anti-Protozoan Agents Having Novel Mode of Action

Masataka Ihara*

*Research Centre of Medicinal Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan

Abstract

Malaria, leishmaniasis, African sleeping sickness (African trypanosomiasis) and Chagas disease (American trypanosomiasis) are caused by different protozoan parasites. Although many people suffer from these diseases in tropical and subtropical areas, efficient medicines against these protozoan diseases are very few or absent. Efforts to develop new drugs against these neglected diseases led us to the discovery of SSJ-127 (62), which cured malaria and African trypanosomiasis mouse models by treatment with injection, SJL-01 (74) as a hit compound for leishmaniasis, and SSJ-183 (109) as a candidate against malaria, respectively. These compounds displayed novel modes of actions different from those of conventional medicines.

■ A Facile Synthesis of Symmetrical and Unsymmetrical Bis(indolyl)acetamides Mediated by Protic Acid

Hai Shang, Fei-Yue Hao, Li Pan, Hong Chen,* and Mao-Sheng Cheng*

*The Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China

Abstract

We report the preparation of symmetrical bis(indolyl)acetamides using the dimerization of 2-hydroxy-(2-indolyl)acetamides and unsymmetrical bis(indolyl)acetamides via electrophilic substitution of indoles with 2-hydroxy-(2-indolyl)acetamides. Both conversions were mediated by protic acid in THF at room temperature.

■ A Practical Synthesis of Novel Rho-Kinase Inhibitor, (S)-4-Fluoro-5-(2-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline

Noriaki Gomi, Tadaaki Ohgiya, Kimiyuki Shibuya,* Jyunji Katsuyama, Masayuki Masumoto, and Hitoshi Sakai

*Pharmaceutical Division, Tokyo New Drug Research Laboratories, Kowa Co., Ltd., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan

Abstract

A practical synthesis of novel Rho-kinase inhibitor, (S)-4-fluoro-5-(2-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline hydrochloride dihydrate (1) was achieved in a pilot-scale production. We have demonstrated the regioselective chlorosulfonylation of 4-fluoroisoquinoline in an one-pot reaction to afford 4-fluoroisoquinoline-5-sulfonyl chloride and the asymmetric construction of the (S)-2-methyl-1,4-diazepane moiety as key steps.

■ Synthesis of Peroxylactones Using Mn(III)-Catalyzed Aerobic Oxidation

Md. Aminul Haque and Hiroshi Nishino*

*Graduate School of Science and Technology, Kumamoto University, Kurokami 2-39-1, Kumamoto 860-8555, Japan

Abstract

The aerobic oxidation of tetronic acid in the presence of 1,1-disubstituted alkenes afforded hydroperoxyethyl-peroxylactones, while a similar reaction using 3-alkyl-substituted tetronic acids gave stable crystalline peroxylactones in good to excellent yields. The oxidation using a stoichiometric amount of manganese(III) acetate did not give the bicyclic lactone but the ethenyl- and/or ethyl-tetronic acid derivatives.

■ Synthesis and Substitution Reactions of 4(6)-Chlorodihydropyrimidines

Hidetsura Cho,* Yoshizumi Yasui, Satoshi Kobayashi, Eunsang Kwon, Mieko Arisawa, and Masahiko Yamaguchi

*Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan

Abstract

Chlorination of the corresponding ketones with phenylphosphonic dichloride (PhPOCl2) provided ethyl 6(4)-chloro-2-methyl-4(6)-phenyl-1,4(6)-dihydropyrimidine-5-carboxylate in good yield. The cross-coupling reactions of organoboronic acids or triethylborane with 1-tert-butyl 5-ethyl 4-chloro-2-methyl-6-phenyl-1,6-dihydropyrimidine-1,5-dicarboxylate synthesized by regiospecific alkoxycarbonylation of the chlorinated dihydropyrimidine afforded 1,4(3,4)-dihydropyrimidines having a variety of functional groups at position-6(4) in good to excellent yields.

■ Pyrido- and Quino-1,2,4-thiadiazine S,S-Dioxides from Reactions of 4-Chloro-3-pyridinesulfonyl- and 4-Chloro-3-quinolinesulfonyl Chlorides with O-Methylisourea

Elwira Chrobak, Michał Wlekliński, Andrzej Maślankiewicz,* Joachim Kusz, Maciej Zubko, and Ewa Michalik

*Department of Organic Chemistry, Medical University of Silesia, Jagiellońska 4, 41-200 Sosnowiec, Poland

Abstract

Reaction of 4-chloro-3- pyridine- (or quinoline)sulfonyl chlorides (1) or (6) with O-methylisourea led to 4-chloro-3-pyridinesulfonyl-O-methylisourea (2a) or its quinoline analog 2b, respectively. Compounds 2a and 2b underwent dehydrochlorination to the title methoxy-pyrido or quino[4,3-e]-1,2,4-thiadiazine S,S-dioxides (3 and 7). X-Ray studies proved that both methoxy derivatives (3 and 7) exist as γazine-NH-tautomers. Reaction of N-H derivatives 3 and 7 with CH3I/CH3OK/DMF system proceeded at the pyridine-ring nitrogen and led to 7-methylpyrido derivative 4a or the 6-methylquino derivative 8a, respectively. After treatment with PhOP(O)Cl2 at 120-150 ºC compounds 4a or 8a were converted to chloro derivatives 4b or 8b, respectively, which were then transformed to aminothiadiazines 5a,b,c or 9a,b,c.

■ Synthesis of Novel Tetrahydro[4,5]imidazo[2,1-b]chromeno[4,3,2-de]quinazoline and Benzothiazol-2-ylaminoxanthenone Derivatives

Mina Saeedi,* Yahya S. Beheshtiha, Majid M. Heravi,* and Hossein A. Oskooie

*Department of Chemistry, School of Sciences, Alzahra University, Vanak, Tehran, Iran

Abstract

Some novel tetrahydroquinazoline and xanthenone derivatives were synthesized from the reaction of dimedone and Schiff base in the presence of sulfamic acid in good yields.

■ Synthesis of the Identical Linker Mode Twin-Drug Type C2-Symmetrical Molecules

Fumiko Fujisaki, Haruka Usami, Saya Nakashima, Shiomi Iwashita, Yurie Kurose, Nobuhiro Kashige, Fumio Miake, and Kunihiro Sumoto*

*Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan

Abstract

In connection with our studies on antibacterial active compounds against gram-positive (Staphylococcus aureus) and gram-negative (Escherichia coli) strains, some molecular modifications were attempted. In this study, molecular transformations of aminoguanidines and related amines to the represented C2-symmetrical molecules (Aa–b, Ba–b, and Ca–b) were investigated. In addition, some C3-symmetrical compounds (Da–b) were also prepared.

■ Penicitrinols F—I, New Citrinin Derivatives from the Marine-Derived Fungus Penicillium citrinum

Li Chen,* Wei Liu, Kai Huang, Xiao Hu, Zhe-Xiang Fang, Jiu-lin Wu, and Qi-Qing Zhang*

*Institute of Biomedical and Pharmaceutical Technology & College of Chemistry and Chemical Engineering, Fuzhou University, No. 523, Gongye Road, Fuzhou City, 350002, China

Abstract

Four new citrinin derivatives, namely, penicitrinols F, G, H, and I (1–4), along with four known compounds, namely, 4,6-dihydroxy-2,3-dimethyl-benzaldehyde (5), pennicitrinone A (6), dicitrinone B (7), and dicitrinone C (8), were isolated from the marine-derived fungus Penicillium citrinum. Their structures were established using spectroscopic methods.

■ The Norphthalocyanines Bearing Two TTF Units: Synthesis, Photophysical and Electrochemical Properties

Ruibin Hou, Cuiping Jiang, Tie Chen, Long-Yi Jin, and Bingzhu Yin*

*Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Yanbian University, Yanji 133002, China

Abstract

A magnesium norphthalocyanine (6a) was prepared by the mixed condensation of phthalonitrile in excess with the dithiomaleonitrile bearing two TTF units (5), using Mg(I1) as a template. Subsequent demetalation of 6a with acetic acid gave 6b in good yield. The structures of target compounds were determined by EA, NMR and TOF MS and their electrochemical and optical properties were also studied by cyclic voltammetry and UV-vis spectroscopy.

■ Two New Eujindoles from Eupenicillium javanicum

Shou Nakadate, Koohei Nozawa,* and Takashi Yaguchi

*School of Pharmaceutical Sciences, Ohu University, 31-1 Misumido, Tomita-machi, Koriyama, Fukushima 963-8611, Japan

Abstract

Two new indole diterpenes, 8,21-dehydro-17-hydroxyeujindole (3) and 8,21-dehydro-17,20-epoxyeujindole (4) were isolated from the extract of Eupenicillium javanicum IFM 59075. The structures were determined by spectroscopic methods.

■ Annulation and Evaluation of Antibacterial Activity of the New Fused Tricyclic (5,5,6) Ring System of Pyrazolo[1,5-c]-1,2,4-triazolo[4,3-a]pyrimidines

Kamal F. M. Atta,* Mohamed G. Marei, Somia M. Abd El-Magiad, and Faten H. A. El-Nashar

*Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 21321, Egypt

Abstract

A series of the new fused 5-aryl-8-phenyl-2H-pyrazolo[1,5-c]-1,2,4-triazolo[4,3-a]pyrimidine-3-thiones 2 were prepared in excellent yields by the reaction of 5-aryl-7-hydrazino-2-phenylpyrazolo[1,5-c]pyrimidines 1 with carbon disulfide in the presence of potassium hydroxide. The pyrazolotriazolopyrimidinethiones gave with certain electrophiles the respective 6-substituted 3-thiones 4-6 rather than the 7-substituted isomeric structure 7. Oxidation of 2 with sodium nitrite or benzenediazonuim chloride afforded the corresponding disulfides 9 or 10 respectively. Moreover, the pyrazolotriazolopyrimidinones 8 were prepared upon reaction with alkaline hydrogen peroxide. All the above compounds were evaluated as antibacterial agents against a variety of microorganisms.

■ Synthesis of Furo[2,3-c]pyridine

Meng-Yang Chang* and Hang-Yi Tai

*Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.

Abstract

A new synthetic strategy toward furo[2,3-c]pyridine (1) starting with N-benzenesulfonylpiperidin-4-one (2) in good yield is described. A synthesis ofazasuger analog 9 is also prepared.

■ Two New Xanthone Glucosides from Swertia mussotii Franch

Lu Gao, Yongfu Zhou, Haiying Yan, Feiyan Huang, Rongrong Wen, and Ganpeng Li*

*Key Laboratory of Ethnic Medicine Resource Chemistry, State Ethnic Affairs Commission & Ministry of Education, School of Chemistry and Biotechnology, Yunnan University of Nationalities, Kunming 650031, China

Abstract

Two new xanthone glucosides, 1-O-β-D-glucopyranosyl-3,5,6-trimethoxy-xanthone (1), 1-O-[β-D-xylopyranosyl-(1→6)-β-D-glucopyranosyl]-3,5,6-trimethoxy-xanthone (2), were isolated from a EtOH extract of the overground parts of Swertia mussotii Franch,which is a traditional Tibet medicine. Their structures were elucidated by spectroscopic methods as well as by chemical studies. Compound 1 showed α-glucosidase inhibitory activity, while compound 2 showed DPP-IV (Dipeptidyl Peptidase IV) inhibitory activity.

■ Metacolchicine, a New Colchicinoid from Sandersonia aurantiaca

Mariko Kitajima, Akiko Tanaka, Noriyuki Kogure, and Hiromitsu Takayama*

*Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan

Abstract

Metacolchicine is a new colchicinoid isolated from the tubers of Sandersonia aurantiaca. Its unique structure featuring an additional carbon unit at C-10 position was deduced from spectroscopic analyses.